Language：English  

DOI： 10.1073/pnas.96.13.7456

Language：English  

DOI： 10.3892/ijo.2024.5701

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PubMed

DOI： 10.1002/ags3.12882

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Language：English  

DOI： 10.1016/j.radcr.2024.07.144

PubMed

Language：English   Publisher：Transplantation  

Background. The consensus that portal venous pressure modulation, including splenectomy (Spx), prevents portal hypertension-related complications after living-donor liver transplantation (LDLT) has been established. However, little evidence about the risk factors for graft loss after simultaneous Spx during LDLT is available. This study aimed to identify the independent predictors of graft loss after simultaneous Spx during LDLT. Methods. Data of 655 recipients who underwent LDLT between 1997 and 2021 were collected and separated into the simultaneous Spx group (n=461) and no-Spx group (n=194). Results. The simultaneous Spx group had significantly lower serum total bilirubin levels, drained ascites volumes, and prothrombin time-international normalized ratios on postoperative day 14 than the no-Spx group (P<0.001 for each). Incidences of small-for-size graft syndrome (P<0.001), acute cellular rejection (P=0.002), and sepsis (P=0.007) were significantly lower in the Spx group. Graft survival of the Spx group was significantly better than that of the no-Spx group (P<0.001; hazard ratio [HR], 1.788; 95% confidence interval, 1.214-2.431). A multivariate analysis revealed that 3 variables, platelet count ≤4.0×104/mm3 (P=0.029; HR, 2.873), donor age ≥60 y old (P=0.013; HR, 6.693), and portal venous pressure at closure ≥20 mm Hg (P=0.010; HR, 3.891), were independent predictors of graft loss within 6 mo after simultaneous Spx during LDLT. Conclusions. Spx is a safe inflow modulation procedure with a positive impact on both postoperative complications and prognosis for most patients. However, patients with the 3 aforementioned independent factors could experience graft loss after LDLT.

DOI： 10.1097/TP.0000000000004952

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PubMed

Language：English   Publisher：John Wiley & Sons Australia, Ltd  

Language：English   Publisher：Cancer Science  

Bromodomain and extraterminal domain (BET) family proteins are epigenetic master regulators of gene expression via recognition of acetylated histones and recruitment of transcription factors and co-activators to chromatin. Hence, BET family proteins have emerged as promising therapeutic targets in cancer. In this study, we examined the functional role of bromodomain containing 3 (BRD3), a BET family protein, in colorectal cancer (CRC). In vitro and vivo analyses using BRD3-knockdown or BRD3-overexpressing CRC cells showed that BRD3 suppressed tumor growth and cell cycle G1/S transition and induced p21 expression. Clinical analysis of CRC datasets from our hospital or The Cancer Genome Atlas revealed that BET family genes, including BRD3, were overexpressed in tumor tissues. In immunohistochemical analyses, BRD3 was observed mainly in the nucleus of CRC cells. According to single-cell RNA sequencing in untreated CRC tissues, BRD3 was highly expressed in malignant epithelial cells, and cell cycle checkpoint-related pathways were enriched in the epithelial cells with high BRD3 expression. Spatial transcriptomic and single-cell RNA sequencing analyses of CRC tissues showed that BRD3 expression was positively associated with high p21 expression. Furthermore, overexpression of BRD3 combined with knockdown of, a driver gene in the BRD family, showed strong inhibition of CRC cells in vitro. In conclusion, we demonstrated a novel tumor suppressive role of BRD3 that inhibits tumor growth by cell cycle inhibition in part via induction of p21 expression. BRD3 activation might be a novel therapeutic approach for CRC.

DOI： 10.1111/cas.16129

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PubMed

Language：English   Publisher：John Wiley & Sons Australia, Ltd  

Language：English   Publisher：Cancer Science  

Considering the cost and invasiveness of monitoring postoperative minimal residual disease (MRD) of colorectal cancer (CRC) after adjuvant chemoradiotherapy (ACT), we developed a favorable approach based on methylated circulating tumor DNA to detect MRD after radical resection. Analyzing the public database, we identified the methylated promoter regions of the genes FGD5, GPC6, and MSC. Using digital polymerase chain reaction (dPCR), we termed the “amplicon of methylated sites using a specific enzyme” assay as “AMUSE.” We examined 180 and 114 pre- and postoperative serial plasma samples from 28 recurrent and 19 recurrence-free pathological stage III CRC patients, respectively. The results showed 22 AMUSE-positive of 28 recurrent patients (sensitivity, 78.6%) and 17 AMUSE-negative of 19 recurrence-free patients (specificity, 89.5%). AMUSE predicted recurrence 208 days before conventional diagnosis using radiological imaging. Regarding ACT evaluation by the reactive response, 19 AMUSE-positive patients during their second or third blood samples showed a significantly poorer prognosis than the other patients (p = 9E-04). The AMUSE assay stratified four groups by the altered patterns of tumor burden postoperatively. Interestingly, only 34.8% of cases tested AMUSE-negative during ACT treatment, indicating eligibility for ACT. The AMUSE assay addresses the clinical need for accurate MRD monitoring with universal applicability, minimal invasiveness, and cost-effectiveness, thereby enabling the timely detection of recurrences. This assay can effectively evaluate the efficacy of ACT in patients with stage III CRC following curative resection. Our study strongly recommends reevaluating the clinical application of ACT using the AMUSE assay.

DOI： 10.1111/cas.16149

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PubMed

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3389/fonc.2024.1340419.

Language：English   Publisher：Annals of Gastroenterological Surgery  

DOI： 10.1002/ags3.12811

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PubMed

Language：English   Publisher：eBioMedicine  

Background: Cell–cell interaction factors that facilitate the progression of adenoma to sporadic colorectal cancer (CRC) remain unclear, thereby hindering patient survival. Methods: We performed spatial transcriptomics on five early CRC cases, which included adenoma and carcinoma, and one advanced CRC. To elucidate cell–cell interactions within the tumour microenvironment (TME), we investigated the colocalisation network at single-cell resolution using a deep generative model for colocalisation analysis, combined with a single-cell transcriptome, and assessed the clinical significance in CRC patients. Findings: CRC cells colocalised with regulatory T cells (Tregs) at the adenoma–carcinoma interface. At early-stage carcinogenesis, cell–cell interaction inference between colocalised adenoma and cancer epithelial cells and Tregs based on the spatial distribution of single cells highlighted midkine (MDK) as a prominent signalling molecule sent from tumour epithelial cells to Tregs. Interaction between MDK-high CRC cells and SPP1+ macrophages and stromal cells proved to be the mechanism underlying immunosuppression in the TME. Additionally, we identified syndecan4 (SDC4) as a receptor for MDK associated with Treg colocalisation. Finally, clinical analysis using CRC datasets indicated that increased MDK/SDC4 levels correlated with poor overall survival in CRC patients. Interpretation: MDK is involved in the immune tolerance shown by Tregs to tumour growth. MDK-mediated formation of the TME could be a potential target for early diagnosis and treatment of CRC. Funding: Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Science Research; OITA Cancer Research Foundation; AMED under Grant Number; Japan Science and Technology Agency (JST); Takeda Science Foundation; The Princess Takamatsu Cancer Research Fund.

DOI： 10.1016/j.ebiom.2024.105102

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PubMed

Language：Japanese   Publisher：The Japan Broncho-esophagological Society  

DOI： 10.2468/jbes.75.67

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.ebiom.2024.105102.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s00595-023-02732-7.

Language：English   Publisher：シュプリンガー・ジャパン(株)  

手術室と遠隔地にそれぞれ触覚フィードバック付きの術者用コンソールを設置し、遠隔手術における触覚フィードバックの有用性を検証し、さらに遠隔ロボット手術の安全性向上を目的として、動物実験を行った。術者用コンソールは福岡市と別府市の手術室に設置し、3段階の触覚フィードバックレベルをランダム順に設定した。術者(現地5名、遠隔地5名)を盲検化し、各触覚レベルでロボット鉗子によりブタの腸を把持する、持ち上げる、下げる、離すという一連の動作を10回繰り返してもらった。その結果、課題の精度や平均把持力には、術者の場所による顕著な差は見られなかった。しかし、遠隔地の場合は現地よりも平均課題完了時間が有意に長く、system usability scaleが有意に低かった。触覚フィードバックレベル間で、課題の精度や課題完了時間に顕著な差はなかったが、触覚フィードバックがある場合はない場合よりも有意に弱い力で臓器を把持することができた。さらに、触覚フィードバックがある場合、ロボット手術の経験が豊富な外科医は、経験の浅い外科医よりも弱い把持力で同等のタスクを行う傾向があった。

Language：English   Publisher：Surgery Today  

Purpose: To verify the usefulness of haptic feedback in telesurgery and improve the safety of telerobotic surgery. Methods: The surgeon's console was installed at two sites (Fukuoka and Beppu; 140 km apart), and the patient cart was installed in Fukuoka. During the experiment, the surgeon was blinded to the haptic feedback levels and asked to grasp the intestinal tract in an animal model. The surgeon then performed the tasks at each location. Results: No marked differences in task accuracy or average grasping force were observed between the surgeon locations. However, the average task completion time was significantly longer, and the system usability scale (SUS) was significantly lower rating for remote operations than for local ones. No marked differences in task accuracy or task completion time were observed between the haptic feedback levels. However, with haptic feedback, the organ was grasped with a significantly weaker force than that without it. Furthermore, with haptic feedback, experienced surgeons in robotic surgery tended to perform an equivalent task with weaker grasping forces than inexperienced surgeons. Conclusion: The haptic feedback function is a tool that allows the surgeon to perform surgery with an appropriate grasping force, both on site and remotely. Improved safety is necessary in telesurgery; haptic feedback will thus be an essential technology in robotic telesurgery going forward.

DOI： 10.1007/s00595-023-02732-7

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Language：English   Publisher：Breast Cancer  

Liquid biopsy using circulating tumor DNA (ctDNA) has been reported to be less invasive and effective for comprehensive genetic analysis of heterogeneous solid tumors, including decision-making for therapeutic strategies, predicting recurrence, and detecting genetic factors related to treatment resistance in various types of cancers. Breast cancer, colorectal cancer, and lung cancer are among the most prevalent malignancies worldwide, and clinical studies of liquid biopsy for these cancers are ongoing. Liquid biopsy has been used as a companion diagnostic tool in clinical settings, and research findings have accumulated, especially in cases of colorectal cancer after curative resection and non-small cell lung cancer (NSCLC) after curative chemoradiotherapy, in which ctDNA detection helps predict eligibility for adjuvant chemotherapy. Liquid biopsy using ctDNA shows promise across a wide range of cancer types, including breast cancer, and its clinical applications are expected to expand further through ongoing research. In this article, studies on liquid biopsy in breast cancer, colorectal cancer, and NSCLC are compared focusing on ctDNA.

DOI： 10.1007/s12282-024-01556-8

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PubMed

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/cas.16149.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s12282-024-01556-8.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/cas.16129.

Language：English   Publisher：The Japanese Society of Balneology, Climatology and Physical Medicine  

DOI： 10.11390/onki.87_1.3

CiNii Research

Language：English   Publisher：Frontiers in Oncology  

Here, we present the case of a 42-year-old female who developed acute pancreatitis due to dexamethasone during adjuvant chemotherapy for early triple negative breast cancer (TNBC). The patient received partial mastectomy and sentinel lymph node biopsy for early TNBC (cT1N0M0, cStage I) of the left breast. Dose-dense doxorubicin plus cyclophosphamide (ddAC) was administered as the adjuvant-chemotherapy; however, epigastralgia appeared on the fifth day of the first administration. A blood test showed a remarkable increase of serum pancreatic enzyme levels and computed tomography (CT) showed the swelling of pancreas and surrounding effusion, and she was diagnosed with moderate acute pancreatitis. As she had no history of excessive alcohol consumption or complication of cholelithiasis, dyslipidemia, or pancreatic neoplasm, drug-induced pancreatitis was suspected. Dexamethasone, which was administered as an antiemetic, was the suspected drug based on the drug administration history and previous report, and dexamethasone was discontinued from the second administration of ddAC. There was subsequently no recurrence of pancreatitis with no increase in serum pancreatic enzyme levels, and it was possible to complete adjuvant-chemotherapy. Alcohol, gallstones, dyslipidemia, and drugs have been reported as causes of pancreatitis; however, steroid-induced acute pancreatitis is extremely rare. We present the first case of acute pancreatitis induced by dexamethasone as the antiemetic.

DOI： 10.3389/fonc.2024.1340419

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PubMed

Language：English  

DOI： 10.1186/s40792-024-01820-1

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PubMed

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1097/TP.0000000000004952.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1186/s40792-024-01820-1.

Language：English   Publisher：Springer Berlin Heidelberg  

49歳男性。特に既往や家族歴、飲酒歴、ウイルス感染歴などなかった。定期検診の腹部超音波検査で肝S7/8に2cm径の腫瘍および軽度の脂肪肝を伴う低エコー病変が認められた。単純CTでは高吸収域を示した。MRIでは、腫瘍はT1強調画像で境界部に高信号、内部に低信号を呈し、T2強調画像では低信号を示した。Gd-EOB-DTPA造影MRIでは、病変に脂肪が含まれており、EOB取り込みも認められた。以上より高分化型肝細胞癌(HCC)を疑い、腹腔鏡下S7/8部分切除術を施行した。患者は術後10日目に合併症なく退院した。病理組織検査の結果、過形成性病変や腺腫などの腫瘍性病変は認められず、肝小葉壊死を伴う再生性肝変化と診断した。

Language：English   Publisher：Cancer Science  

The Japan Diabetes Society and the Japan Cancer Association launched a joint committee and published their “First Joint Committee Report on Diabetes and Cancer” in 2013, compiling recommendations for physicians and health-care providers as well as for the general population. In 2016, the “Second Joint Committee Report on Diabetes and Cancer” summarized the current evidence on glycemic control and cancer risk in patients with diabetes. The current “Third Joint Committee Report on Diabetes and Cancer”, for which the joint committee also enlisted the assistance of the Japanese Society of Clinical Oncology and the Japanese Society of Medical Oncology, reports on the results from the questionnaire survey, “Diabetes Management in Patients Receiving Cancer Therapy,” which targeted oncologists responsible for cancer management and diabetologists in charge of glycemic control in cancer patients. The results of the current survey indicated that there is a general consensus among oncologists and diabetologists with regard to the need for guidelines on glycemic control goals, the relevance of glycemic control, and glycemic control during cancer therapy in cancer patients.

DOI： 10.1111/cas.15975

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PubMed

Language：English   Publisher：Diabetology International  

The Japan Diabetes Society (JDS) and the Japan Cancer Association (JCA) launched a joint committee and published their “First Joint Committee Report on Diabetes and Cancer” in 2013, compiling recommendations for physicians and healthcare providers as well as for the general population. In 2016, the “Second Joint Committee Report on Diabetes and Cancer” summarized the current evidence on glycemic control and cancer risk in patients with diabetes. The current “Third Joint Committee Report on Diabetes and Cancer”, for which the joint committee also enlisted the assistance of the Japanese Society of Clinical Oncology (JSCO) and the Japanese Society of Medical Oncology (JSMO), reports on the results from the questionnaire survey, “Diabetes Management in Patients Receiving Cancer Therapy,” which targeted oncologists responsible for cancer management and diabetologists in charge of glycemic control in cancer patients. The results of the current survey demonstrated that there is a general consensus among oncologists and diabetologists with regard to the need for guidelines on glycemic control goals, the relevance of glycemic control, and glycemic control during cancer therapy in cancer patients.

DOI： 10.1007/s13340-023-00672-8

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PubMed

Language：Japanese   Publisher：Japanese Society for Molecular Tumor Marker Research  

DOI： 10.11241/jsmtmr.39.18

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s00464-023-10521-z.

Publisher：Science Advances  

Head-and-neck squamous cell carcinoma (HNSCC) is the sixth most common group of cancers in the world, and patients have a poor prognosis. Here, we present data indicating that YAP1 may be a strong driver of the onset and progression of oral SCC (OSCC), a major subtype of HNSCC. Mice with tongue-specific deletion of Mob1a/b and thus endogenous YAP1 hyperactivation underwent surprisingly rapid and highly reproducible tumorigenesis, developing tongue carcinoma in situ within 2 weeks and invasive SCC within 4 weeks. In humans, precancerous tongue dysplasia displays YAP1 activation correlating with reduced patient survival. Combinations of molecules mutated in OSCC may increase and sustain YAP1 activation to the point of oncogenicity. Strikingly, siRNA or pharmacological inhibition of YAP1 blocks murine OSCC onset in vitro and in vivo. Our work justifies targeting YAP1 as therapy for OSCC and perhaps HNSCC, and our mouse model represents a powerful tool for evaluating these agents.

DOI： 10.1126/sciadv.adn0844

Scopus

Language：English   Publisher：Case Reports in Oncology  

Here, we present a 69-year-old female with advanced neuroendocrine carcinoma (NEC) of colon with multiple liver, bone, and kidney metastases who developed Trousseau's syndrome. The patient received etoposide plus cisplatin (EP) as the first-line therapy; however, after single administration of EP, she developed the severe lower-limb edema and EP was considered to be intolerable. Etoposide plus carboplatin was administered as the second-line therapy and after 3 cycles of administration, the progressive disease (PD) was confirmed and 5-fluorouracil + leucovorin + irinotecan (FOLFIRI) plus ramucirumab was administered as the third-line therapy. However, PD was confirmed after 3 cycles of the therapy, and she was to receive the best supportive care and was hospitalized in our hospital. Four weeks after hospitalization, mild impaired consciousness and dysarthria were observed. Blood tests showed coagulation abnormalities including elevation of plasma fibrin/fibrinogen degradation products (FDPs) and D-dimer levels, and the diffusion-weighted image of magnetic resonance imaging (MRI) of the head showed multiple cerebral infarcts. She was diagnosed with Trousseau's syndrome due to the progression of NEC and intravenous unfractionated heparin was administered as anticoagulant therapy. After the administration of heparin, plasma FDP and D-dimer levels decreased; however, due to the progression of NEC, the patient died 6 weeks after hospitalization. This is the first report of NEC of the colon that developed Trousseau's syndrome.

DOI： 10.1159/000530927

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PubMed

Language：English   Publisher：Surgical Endoscopy  

Background: In telementoring, differences in teaching methods affect local surgeons’ comprehension. Because the object to be operated on is a three-dimensional (3D) structure, voice or 2D annotation may not be sufficient to convey the instructor’s intention. In this study, we examined the usefulness of telementoring using 3D drawing annotations in robotic surgery. Methods: Kyushu University and Beppu Hospital are located 140 km apart, and the study was conducted using a Saroa™ surgical robot by RIVERFIELD Inc. using a commercial guarantee network on optical fiber. Twenty medical students performed vertical mattress suturing using a swine intestinal tract under surgical guidance at the Center for Advanced Medical Innovation Kyushu University. Surgical guidance was provided by Beppu Hospital using voice, 2D, and 3D drawing annotations. All robot operations were performed using 3D images, and only the annotations were independently switched between voice and 2D and 3D images. The operation time, needle movement, and performance were also evaluated. Results: The 3D annotation group tended to have a shorter working time than the control group (25.6 ± 63.2 vs. − 36.7 ± 65.4 min, P = 0.06). The 3D annotation group had fewer retries than the control group (1.3 ± 1.7 vs. − 1.1 ± 0.7, P = 0.006), and there was a tendency for fewer needle drops (0.4 ± 0.7 vs. − 0.5 ± 0.9, P = 0.06). The 3D annotation group scored significantly higher than the control group on the Global Evaluate Assessment of Robot Skills (16.8 ± 2.0 vs. 22.8 ± 2.4, P = 0.04). The 3D annotation group also scored higher than the voice (13.4 ± 1.2) and 2D annotation (16.2 ± 1.8) groups (3D vs. voice: P = 0.03, 3D vs. 2D: P = 0.03). Conclusion: Telementoring using 3D drawing annotation was shown to provide good comprehension and a smooth operation for local surgeons. Graphical abstract: [Figure not available: see fulltext.]

DOI： 10.1007/s00464-023-10521-z

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1245/s10434-023-13864-y.

DOI： 10.1245/s10434-023-14037-7

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PubMed

Language：English   Publisher：Annals of Surgical Oncology  

Background: Endoplasmic reticulum (ER) stress has a close relation with cancer progression. Blocking the adaptive pathway of ER stress could be an anticancer strategy. Here, we identified an ER stress-related gene, Transducin beta-like 2 (TBL2), an ER-localized type I transmembrane protein, on increased chromosome 7q as a candidate driver gene of lung adenocarcinoma (LUAD). Methods: The association between TBL2 mRNA expression and prognostic outcomes and clinicopathological factors was analyzed using The Cancer Genome Atlas (TCGA) datasets of LUAD and lung squamous cell carcinoma (LUSC). Localization of TBL2 in tumor tissues was observed by immunohistochemical staining. Gene set enrichment analysis (GSEA) was conducted using TCGA dataset. In vitro cell proliferation assays were performed using TBL2 knockdown LUAD cells, LUSC cells, and LUAD cells overexpressing TBL2. Apoptosis and ATF4 expression (ER stress marker) were evaluated by western blotting. Results: TBL2 was overexpressed in LUAD and LUSC cells. Multivariate analysis indicated high TBL2 mRNA expression was an independent poor prognostic factor of LUAD. GSEA revealed high TBL2 expression was positively correlated to the ER stress response in LUAD. TBL2 knockdown attenuated LUAD cell proliferation under ER stress. TBL2 inhibited apoptosis in LUAD cells under ER stress. TBL2 knockdown reduced ATF4 expression under ER stress. Conclusions: TBL2 may be a novel driver gene that facilitates cell proliferation, possibly by upregulating ATF4 expression followed by adaptation to ER stress, and it is a poor prognostic biomarker of LUAD.

DOI： 10.1245/s10434-023-13864-y

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Language：English   Publisher：British Journal of Cancer  

Background: Intratumor heterogeneity (ITH) in microsatellite instability-high (MSI-H) colorectal cancer (CRC) has been poorly studied. We aimed to clarify how the ITH of MSI-H CRCs is generated in cancer evolution and how immune selective pressure affects ITH. Methods: We reanalyzed public whole-exome sequencing data on 246 MSI-H CRCs. In addition, we performed a multi-region analysis from 6 MSI-H CRCs. To verify the process of subclonal immune escape accumulation, a novel computational model of cancer evolution under immune pressure was developed. Results: Our analysis presented the enrichment of functional genomic alterations in antigen-presentation machinery (APM). Associative analysis of neoantigens indicated the generation of immune escape mechanisms via HLA alterations. Multiregion analysis revealed the clonal acquisition of driver mutations and subclonal accumulation of APM defects in MSI-H CRCs. Examination of variant allele frequencies demonstrated that subclonal mutations tend to be subjected to selective sweep. Computational simulations of tumour progression with the interaction of immune cells successfully verified the subclonal accumulation of immune escape mutations and suggested the efficacy of early initiation of an immune checkpoint inhibitor (ICI) -based treatment. Conclusions: Our results demonstrate the heterogeneous acquisition of immune escape mechanisms in MSI-H CRCs by Darwinian selection, providing novel insights into ICI-based treatment strategies.

DOI： 10.1038/s41416-023-02395-8

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41416-023-02395-8.

Language：English  

DOI： 10.1007/s13691-023-00618-6

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Language：English   Publisher：シュプリンガー・ジャパン(株)  

症例は90歳女性。非B非C型肝炎であり、18ヵ月前に原発性肝細胞癌に対して腹腔鏡下肝切除術が施行された。術後6ヵ月、肝細胞癌再発に対して経カテーテル的肝動脈化学塞栓療法(TACE)が施行されたが、その1年後に2回目の再発が認められた。レンバチニブ(LEN)8mg/日投与を開始したところ、1週間後に極度の疲労や食欲不振などの重篤な有害事象(AE)が出現し、投与量を4mg/日に減量したがAEの管理は困難であった。そこで、LEN導入から1ヵ月後に化学療法をアテゾリズマブ+ベバシズマブ併用療法に変更した。その結果、副作用はほとんど認められず、腫瘍の退縮が認められた。本レジメンを8ヵ月間、10サイクル続け、最終的に完全奏効(CR)を達成した。CR達成後1年経過しても再発はみられていない。

Language：English  

DOI： 10.1186/s40792-023-01751-3

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PubMed

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1186/s40792-023-01751-3.

Language：English   Publisher：Springer Berlin Heidelberg  

症例は14歳男児で、虫垂炎の評価のため行った腹部CTで28mm大の肝腫瘍が検出され、次第に増大した。当科紹介時の腹部CTでは35mm大の固形腫瘍と、右門脈の閉塞および腫瘍内の石灰化が認められた。悪性のfibrolamellar hepatocellular carcinoma(FL-HCC)と診断し、右肝切除を行った。術後経過は良好で、術後9日目に退院した。病理組織学的所見では、腫瘍のcentral scarは過形成と線維化を示し、ヒアリン石灰化を伴っていた。腫瘍細胞には肥大した核と明瞭な核小体、好酸性顆粒状細胞質が認められ、切除リンパ節に腫瘍細胞の転移がみられ、FL-HCCと診断した。初回手術から12ヵ月後に肝十二指腸間膜靱帯で単発のリンパ節再発を認め、再発腫瘍に対してリンパ節切除を行った。切除標本(原発巣、リンパ節転移巣、正常肝)を用いてRNAシークエンシング(RNA-seq)と標的遺伝子の変異解析を行った。RNA-seqでは、原発巣と転移巣の両方でDNAJB1-PRKACAが検出された。本症例の遺伝子発現は過去のFL-HCC症例と類似していたが、若年患者のHCC症例とは異なるクラスターであった。

Language：English   Publisher：Annals of Gastroenterological Surgery  

Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) was first proposed by Wothley et al. in 2012 as a rare familial gastric cancer syndrome associated with an autosomal dominant form of inheritance. GAPPS is characterized by gastric basal gland polyposis from the hilum to the body of the stomach. Li et al. in 2016 showed that the cause of the disease is a point mutation in the promotor 1B region of the APC gene, and genetic testing was used to confirm the diagnosis. If the patient has already developed gastric cancer, treatment should be based on the usual treatment for gastric cancer. If no distant metastases exist, a good prognosis can be expected by performing a total gastrectomy. On the other hand, patients with distant metastasis have a poor prognosis. In the case of dysplasia, prophylactic total gastrectomy is recommended, but because it is highly invasive and postoperative postgastrectomy syndrome must be considered, the decision should be made with careful consideration of the patient's background. Therefore, there are no guidelines for screening for GAPPS, the timing of prophylactic total gastrectomy, or methods of endoscopic surveillance. Because GAPPS is a rare disease, its natural history is still unclear. Further case series are needed to elucidate the molecular biology and clinicopathological features of GAPPS and to establish clinical management, including diagnosis, treatment, and surveillance. In this review, we provide an overview of GAPPS, its clinical management, and its problems, which will be useful for the treatment of GAPPS.

DOI： 10.1002/ags3.12708

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Language：English   Publisher：Heliyon  

Hot springs have long been used for medical purposes throughout the world. Recently, the positive effects of hot spa-bathing on circulatory diseases have been reported, while there are few reports on the mental effects of hot spa-bathing. Therefore, the purpose of this study was to clarify the relationship between hot spa-bathing habits and mental health throughout Japan. We conducted a nationwide online survey, including questions on bathing behavior, subjective satisfaction, lifestyle, and illness. The results showed a significant positive correlation between hot spa-bathing habits and multiple subjective satisfaction levels regarding mental health effects. The factor analysis results indicated that hot spa-bathing habits tended to be associated with good mental health, high health consciousness, and disease. Our study revealed that subjective satisfaction was higher among individuals with hot spa-bathing habits, suggesting that the hot spring spa-bathing habit may have a positive influence on mental health.

DOI： 10.1016/j.heliyon.2023.e19631

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.heliyon.2023.e19631.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s00464-023-10061-6.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s13691-023-00618-6.

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DOI： 10.1159/000530927.

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DOI： 10.1002/ags3.12708.

Language：English   Publisher：British Journal of Cancer  

Background: Driver alterations may represent novel candidates for driver gene-guided therapy; however, intrahepatic cholangiocarcinoma (ICC) with multiple genomic aberrations makes them intractable. Therefore, the pathogenesis and metabolic changes of ICC need to be understood to develop new treatment strategies. We aimed to unravel the evolution of ICC and identify ICC-specific metabolic characteristics to investigate the metabolic pathway associated with ICC development using multiregional sampling to encompass the intra- and inter-tumoral heterogeneity. Methods: We performed the genomic, transcriptomic, proteomic and metabolomic analysis of 39–77 ICC tumour samples and eleven normal samples. Further, we analysed their cell proliferation and viability. Results: We demonstrated that intra-tumoral heterogeneity of ICCs with distinct driver genes per case exhibited neutral evolution, regardless of their tumour stage. Upregulation of BCAT1 and BCAT2 indicated the involvement of ‘Val Leu Ile degradation pathway’. ICCs exhibit the accumulation of ubiquitous metabolites, such as branched-chain amino acids including valine, leucine, and isoleucine, to negatively affect cancer prognosis. We revealed that this metabolic pathway was almost ubiquitously altered in all cases with genomic diversity and might play important roles in tumour progression and overall survival. Conclusions: We propose a novel ICC onco-metabolic pathway that could enable the development of new therapeutic interventions. [Figure not available: see fulltext.]

DOI： 10.1038/s41416-023-02256-4

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Language：English   Publisher：Surgical Endoscopy  

Background: Although several studies on telesurgery have been reported globally, a clinically applicable technique has not yet been developed. As part of a telesurgical study series conducted by the Japan Surgical Society, this study describes the first application of a double-surgeon cockpit system to telesurgery. Methods: Surgeon cockpits were installed at a local site and a remote site 140 km away. Three healthy pigs weighing between 26 and 29 kg were selected for surgery. Non-specialized surgeons performed emergency hemostasis, cholecystectomy, and renal vein ligation with remote assistance using the double-surgeon cockpits and specialized surgeons performed actual telesurgery. Additionally, the impact of adding internet protocol security (IPsec) encryption to the internet protocol-virtual private network (IP-VPN) line on communication was evaluated to address clinical security concerns. Results: The average time required for remote emergency hemostasis with the double-surgeon cockpit system was 10.64 s. A non-specialized surgeon could safely perform cholecystectomy or renal vein ligation with remote assistance. Global Evaluative Assessment of Robotic Skills and System Usability Scale scores were higher for telesurgical support-assisted surgery by a non-specialized surgeon using the double-surgeon cockpits than for telesurgery performed by a specialized surgeon without the double-cockpit system. Adding IPsec encryption to the IP-VPN did not have a significant impact on communication. Conclusion: Telesurgical support through our double-surgeon cockpit system is feasible as first step toward clinical telesurgery.

DOI： 10.1007/s00464-023-10061-6

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Language：English   Publisher：Molecular Oncology  

Accuracy and transparency of scientific data are becoming more and more relevant with the increasing concern regarding the evaluation of data reproducibility in many research areas. This concern is also true for quantifying coding and noncoding RNAs, with the remarkable increase in publications reporting RNA profiling and sequencing studies. To address the problem, we propose the following recommendations: (a) accurate documentation of experimental procedures in Materials and methods (and not only in the supplementary information, as many journals have a strict mandate for making Materials and methods as visible as possible in the main text); (b) submission of RT-qPCR raw data for all experiments reported; and (c) adoption of a unified, simple format for submitted RT-qPCR raw data. The Real-time PCR Data Essential Spreadsheet Format (RDES) was created for this purpose.

DOI： 10.1002/1878-0261.13418

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PubMed

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1002/1878-0261.13418.

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DOI： 10.21873/cgp.20373.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1002/ags3.12670.

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Language：English   Publisher：Annals of Gastroenterological Surgery  

DOI： 10.1002/ags3.12670

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Language：English   Publisher：Cancer Genomics and Proteomics  

Background/Aim: The immune system has a pivotal role in modulating the response to chemotherapy in breast cancer (BC). However, the immune status during chemotherapy remains unclear. We evaluated the sequential changes in peripheral systemic immunity markers in BC patients treated with various chemotherapeutic agents. Materials and Methods: We examined the correlation between the peripheral systemic immunity markers, neutrophil-to-lymphocyte ratio (NLR), absolute lymphocyte count (ALC) and the local cytolytic activity (CYT) score obtained by quantitative reverse-transcription polymerase chain reaction of 84 preoperative BC patients. Next, we observed the sequential changes in the peripheral systemic immunity markers during treatment with four anticancer drugs: oral 5-fluorouracil derivative; S-1, epirubicin plus cyclophosphamide; paclitaxel plus the anti-vascular endothelial growth factor antibody bevacizumab, and eribulin in 172 HER2-negative advanced BC patients. Finally, we examined the correlation between the changes in the peripheral systemic immunity markers, time to treatment failure (TTF) and progression-free survival (PFS). Results: A negative correlation was found between ALC and NLR. ALC-low and NLR-high cases were positively associated with CYT score-low cases. The ratio of ALC-increase and NLR-decrease varies depending on the anticancer drugs used. The responder group (TTF .3 months) had a higher NLR-decrease ratio than the nonresponder group (TTF <3 months). Patients with a high NLR-decrease ratio showed higher PFS. Conclusion: The change in ALC or NLR varies according to the anticancer drugs, suggesting differential immunomodulatory effects of the drugs. Furthermore, the change in NLR reflects the therapeutic efficacy of chemotherapy in advanced BC.

DOI： 10.21873/cgp.20373

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Language：English   Publisher：Cell Reports  

The cellular interactions in the tumor microenvironment of colorectal cancer (CRC) are poorly understood, hindering patient treatment. In the current study, we investigate whether events occurring at the invasion front are of particular importance for CRC treatment strategies. To this end, we analyze CRC tissues by combining spatial transcriptomics from patients with a public single-cell transcriptomic atlas to determine cell-cell interactions at the invasion front. We show that CRC cells are localized specifically at the invasion front. These cells induce human leukocyte antigen G (HLA-G) to produce secreted phosphoprotein 1 (SPP1)+ macrophages while conferring CRC cells with anti-tumor immunity, as well as proliferative and invasive properties. Taken together, these findings highlight the signaling between CRC cell populations and stromal cell populations at the cellular level.

DOI： 10.1016/j.celrep.2022.111929

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Language：English   Publisher：Scientific Reports  

The detection and sequencing of the mutated ctDNA is one of the irreplaceable clinical measures in the postoperative management of colorectal cancer (CRC) cases. However, we are curious to comprehend the essential traits of mutated genes comprising metastatic sites out of whole mutated genes in primary sites. In the current retrospective study, we conducted target resequencing of ctDNA using 47 plasma samples and established a cancer panel carrying the commonly mutated genes between primary and recurrent tumors. We found that mutated genes in ctDNA indicated immune-resistance traits with respect to the impaired ability to present neoantigens by loss of expression or binding affinity to HLA in the primary tumor. Compared with the estimated neoantigens from all mutated genes in primary tumors, the neoantigen peptides from commonly mutated genes on the panel showed abundant expression but no binding affinity to HLA. Therefore, ctDNA mutations can be frequently and postoperatively detected to identify recurrence; however, these mutated genes were derived from immune-tolerated clones owing to the loss of neoantigen presentation in primary CRC tumors.

DOI： 10.1038/s41598-023-28575-3

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.celrep.2022.111929.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.21873/cgp.20362.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1093/jncics/pkac080.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41598-023-28575-3.

Language：English   Publisher：シュプリンガー・ジャパン(株)  

症例は59歳女性で、他院にてトリプルネガティブ乳癌(cT3NXM0、cStage IIIB、浸潤性乳管癌)と診断され、左乳房切除術と腋窩リンパ節郭清を受けた。手術検体の病理組織学的検査では悪性葉状腫瘍に一致していた。術後4ヵ月、左胸A・B領域の悪性葉状腫瘍再発、最大径5cmの多発性肺転移、リンパ節転移と診断され、当院で全身化学療法を受けることになった。二次化学療法としてパゾパニブを投与した。治療開始2.5ヵ月後、CT検査で肺病変のサイズと空洞が減少したが、新たに左気胸を認めた。立位胸部X線では気胸の鑑別が困難であった。気胸の典型的な症状や身体所見である呼吸困難、胸痛、呼吸音減弱は認めなかった。気胸は小さく無症状であったため、パゾパニブ投与を中止し、胸部X線とCTで経過観察を行った。1週間後、CTで気胸の改善を確認した。化学療法をエリブリンに変更したが、エリブリン初回投与後に肺病変の急速な増大を認めたため、パゾパニブを再投与した。胸部X線とCTによる慎重な経過観察を行った結果、気胸の再発は認めなかった。

Language：English   Publisher：Cancer Genomics and Proteomics  

Background/Aim: Peritoneal metastasis (PM) of gastric cancer (GC) leads to poor clinical outcomes. Tumor-derived exosomes promote metastasis via communication between tumor cells and host cells. In this study, we investigated the effect of Rab27, which is required for exosome secretion, on the PM of GC. Materials and Methods: We established a stable knockdown of two Rab27 homologs, Rab27a and Rab27b, in human GC cells (58As9) with a high potential of PM. We examined the level of exosome secretion from Rab27-knockdown 58As9 cells by Western blotting and the ability of Rab27b knockdown to suppress PM in 58As9 cells using a mouse xenograft model. In vitro proliferation and invasion assays were performed in the Rab27b-knockdown cells. Next, Rab27b expression was evaluated in human GC tissues by immunohistochemistry. Finally, we assessed the clinicopathological and prognostic significance of Rab27b expression by RT-qPCR in both our and other TCGA datasets of GC. Results: Rab27a and Rab27b knockdown in 58As9 cells decreased the secretion of exosomes, characterized by the endocytic marker CD63.

DOI： 10.21873/cgp.20362

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Language：English   Publisher：Annals of Surgical Oncology  

Background: Serum microRNAs (miRNAs) have been recognized as potential stable biomarkers for various types of cancer. Considering the clinical applications, there are certain critical requirements, such as minimizing the number of miRNAs, reproducibility in a longitudinal clinical course, and superiority to conventional tumor markers, such as carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9. This study aimed to identify serum miRNAs that indicate the recurrence of colorectal cancer (CRC), surpassing inter-tumor heterogeneity. Methods: We conducted an analysis of 434 serum samples from 91 patients with CRC and 71 healthy subjects. miRNAs were obtained from Toray Co., Ltd, and miRNA profiles were analyzed using a three-step approach. miRNAs that were highly expressed in patients with CRC than in the healthy controls in the screening phase, and those that were highly expressed in the preoperative samples than in the 1-month postoperative samples in the discovery phase, were extracted. In the validation phase, the extracted miRNAs were evaluated in 323 perioperative samples, in chronological order. Results: A total of 12 miRNAs (miR-25-3p, miR-451a, miR-1246, miR-1268b, miR-2392, miR-4480, miR-4648, miR-4732-5p, miR-4736, miR-6131, miR-6776-5p, and miR-6851-5p) were significantly concordant with the clinical findings of tumor recurrence, however their ability to function as biomarkers was comparable with CEA. In contrast, the combination of miR-1246, miR-1268b, and miR-4648 demonstrated a higher area under the curve (AUC) than CEA. These three miRNAs were upregulated in primary CRC tissues. Conclusion: We identified ideal combinatorial miRNAs to predict CRC recurrence.

DOI： 10.1245/s10434-022-12355-w

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Language：English   Publisher：Annals of Gastroenterological Surgery  

Aim: Gastric mucosal changes associated with chronic gastritis are known to be precancerous lesions of gastric cancer. We aimed to identify individuals with a high risk of gastric cancer by detection of microRNAs (miRNA) in the blood as biomarkers. Methods: Of 1206 individuals screened, 144 who were positive for Helicobacter pylori (H. pylori) by the serum antibody test and who underwent endoscopy were the subjects of this study. For the gross assessment of mucosal inflammation, we applied the Kimura–Takemoto classification, in which normal mucosa was defined as grade 0, and atrophy was categorized as grade 1 (C-1 and C-2), grade 2 (C-3 and O-1), and grade 3 (O-2 and O-3). Serum samples were divided into two phases and used for miRNA microarray profiling. We compared the expression of miRNAs in grade 3 mucosa and other grades. Expression in gastric cancer was confirmed with TCGA data. Results: miR-196b-3p was significantly upregulated, and miR-92a-2-5p was downregulated (P <.05 and q < 0.2). TCGA data showed a high expression of miR-196b-3p in gastric cancer cases (P <.001). Comparing grade 3 and the others, the area under the receiver operating characteristic curve using the detected miRNAs was as high as about 0.7. Furthermore, the combination of miRNAs resulted in higher accuracy. In terms of the significance of the combinatory mRNAs, the combination of three miRNAs (miR-196b-3p, miR-92a-2-5p, and miR-6791-3p) revealed high sensitivity and specificity, with the area under the curve exceeding 0.8. Conclusion: The identified combinatory miRNAs may represent promising biomarkers of precancerous lesions in gastric cancer.

DOI： 10.1002/ags3.12610

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DOI： 10.1007/s13691-022-00572-9

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

本研究の目的は、血中マイクロRNA(miRNA)をバイオマーカーとして検出することで、胃癌リスクの高い症例を同定することである。スクリーニングを行った1206名のうち、血清抗体検査でヘリコバクター・ピロリ(H.pylori)陽性で、内視鏡検査を受けた144名を本研究の対象とした。粘膜炎症の肉眼的評価には、正常粘膜をグレード0、萎縮をグレード1(C-1、C-2)、グレード2(C-3、O-1)、グレード3(O-2、O-3)に分類する木村・竹本分類を適用した。血清サンプルは2相に分け、miRNAマイクロアレイプロファイリングに使用した。グレード3の粘膜とその他のグレードの粘膜におけるmiRNAの発現を比較した。胃癌における発現は、TCGAのデータで確認した。miR-196b-3pは有意に増加し、miR-92a-2-5pは減少していた(P<0.05、q<0.2)。TCGAのデータでは、胃癌症例においてmiR-196b-3pの発現が高いことが示された(P<0.001)。グレード3とそれ以外を比較すると、検出されたmiRNAを用いた受信者動作特性曲線下面積は0.7であった。さらに、miRNAを組み合わせることで、より高い精度が得られた。miRNAを組み合わせる場合、3種類のmiRNA(miR-196b-3p、miR-92a-2-5p、miR-6791-3p)の組み合わせが高い感度と特異性を示し、曲線下面積は0.8を超えていた。ここに示されたmiRNAの組み合わせは、胃癌の前癌病変のバイオマーカーとして有望である可能性がある。

Language：English   Publisher：JGH Open  

Background and Aim: The risk of hepatocellular carcinoma (HCC) persists in a condition of sustained virologic response (SVR) after hepatitis C virus (HCV) eradication. Comprehensive molecular analyses were performed to test the hypothesis that epigenetic abnormalities present after an SVR play a role in hepatocarcinogenesis. Methods: Whole-genome methylome and RNA sequencing were performed on HCV, SVR, and healthy liver tissue. Integrated analysis of the sequencing data focused on expression changes in transcription factors and their target genes, commonly found in HCV and SVR. Identified expression changes were validated in demethylated cultured HCC cell lines and an independent validation cohort. Results: The coincidence rates of the differentially methylated regions between the HCV and SVR groups were 91% in the hypomethylated and 71% in the hypermethylated regions in tumorous tissues, and 37% in the hypomethylated and 36% in the hypermethylated regions in non-tumorous tissues. These results indicate that many epigenomic abnormalities persist even after an SVR was achieved. Integrated analysis identified 61 transcription factors and 379 other genes that had methylation abnormalities and gene expression changes in both groups. Validation cohort specified gene expression changes for 14 genes, and gene ontology pathway analysis revealed apoptotic signaling and inflammatory response were associated with these genes. Conclusion: This study demonstrates that DNA methylation abnormalities, retained after HCV eradication, affect the expression of transcription factors and their target genes. These findings suggest that DNA methylation in SVR patients may be functionally important in carcinogenesis, and could serve as biomarkers to predict HCC occurrence.

DOI： 10.1002/jgh3.12833

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Language：English   Publisher：npj Systems Biology and Applications  

Drugs are expected to recover the cell system away from the impaired state to normalcy through disease treatment. However, the understanding of gene regulatory machinery underlying drug activity or disease pathogenesis is far from complete. Here, we perform large-scale regulome analysis for various diseases in terms of gene regulatory machinery. Transcriptome signatures were converted into regulome signatures of transcription factors by integrating publicly available ChIP-seq data. Regulome-based correlations between diseases and their approved drugs were much clearer than the transcriptome-based correlations. For example, an inverse correlation was observed for cancers, whereas a positive correlation was observed for immune system diseases. After demonstrating the usefulness of the regulome-based drug discovery method in terms of accuracy and applicability, we predicted new drugs for nonsmall cell lung cancer and validated the anticancer activity in vitro. The proposed method is useful for understanding disease–disease relationships and drug discovery.

DOI： 10.1038/s41540-022-00255-4

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Language：English   Publisher：PLoS ONE  

Background Colorectal cancer (CRC) can be classified into four consensus molecular subtypes (CMS) according to genomic aberrations and gene expression profiles. CMS is expected to be useful in predicting prognosis and selecting chemotherapy regimens. However, there are still no reports on the relationship between the morphology and CMS. Methods This retrospective study included 55 subjects with T2 CRC undergoing surgical resection, of whom 30 had the depressed type and 25 the protruded type. In the classification of the CMS, we first defined cases with deficient mismatch repair as CMS1. And then, CMS2/3 and CMS4 were classified using an online classifier developed by Trinh et al. The staining intensity of CDX2, HTR2B, FRMD6, ZEB1, and KER and the percentage contents of CDX2, FRMD6, and KER are input into the classifier to obtain automatic output classifying the specimen as CMS2/3 or CMS4. Results According to the results yielded by the online classifier, of the 30 depressed-type cases, 15 (50%) were classified as CMS2/3 and 15 (50%) as CMS4. Of the 25 protruded-type cases, 3 (12%) were classified as CMS1 and 22 (88%) as CMS2/3. All of the T2 CRCs classified as CMS4 were depressed CRCs. More malignant pathological findings such as lymphatic invasion were associated with the depressed rather than protruded T2 CRC cases. Conclusions Depressed-type T2 CRC had a significant association with CMS4, showing more malignant pathological findings such as lymphatic invasion than the protruded-type, which could explain the reported association between CMS4 CRC and poor prognosis.

DOI： 10.1371/journal.pone.0273566

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Language：English   Publisher：Anticancer Research  

Background/Aim: Alternative splicing plays a vital role in cancer development and progression. The splicing C complex is involved in alternative splicing. However, the role of PRKR-interacting protein 1 (PRKRIP1), a component of the splicing C complex, in colorectal cancer (CRC) remains unclear. This study aimed to determine the clinicopathological, biological and prognostic significance of PRKRIP1 expression in CRC. Materials and Methods: We used a bioinformatics approach to screen for oncogenes using The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia (CCLE) datasets and identified PRKRIP1 as a driver gene on chromosome 7q. The mRNA expression of PRKRIP1 was measured using reverse transcription-quantitative PCR in 165 surgically resected CRC samples in our hospital, and its localization was determined using immunohistochemical staining. Gene Set Enrichment Analysis (GSEA) was performed using TCGA dataset. Results: High PRKRIP1 expression was significantly associated with poor prognosis in both the samples and TCGA dataset. A positive correlation was observed between copy number variation and PRKRIP1 expression in TCGA and CCLE datasets, and the frequency of PRKRIP1 mutations was less than 5%. Immunohistochemistry revealed that PRKRIP1 was located in the cytoplasm of tumor cells. GSEA revealed that PRKRIP1 expression was correlated with apoptosis-related gene sets. Conclusion: PRKRIP1 overexpression may be a poor prognostic biomarker for CRC. Although it is known that PRKRIP1, a spliceosome factor, is essential for splicing, we now revealed the way by which its expression accelerates CRC progression.

DOI： 10.21873/anticanres.15974

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1002/ags3.12610.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s13691-022-00572-9.

Language：English   Publisher：Digestive Diseases and Sciences  

Background: Combined hepatocellular and cholangiocarcinoma is a rare primary liver cancer with histological features of both hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Little is known about the prognostic features and molecular mechanism of cHCC-iCCA. Acylphosphatase 1 is a cytosolic enzyme that produces acetic acid from acetyl phosphate and plays an important role in cancer progression. Aims: We evaluated the clinical significance of ACYP1 expression in cHCC-iCCA, HCC, and iCCA. Methods: ACYP1 immunohistochemistry was performed in 39 cases diagnosed with cHCC-iCCA. The prognosis was evaluated in three different cohorts (cHCC-iCCA, HCC, and iCCA). The relationships between ACYP1 expression and cell viability, migration, invasiveness, and apoptosis were examined using siRNA methods in vitro. In vivo subcutaneous tumor volumes and cell apoptosis were evaluated after downregulation of ACYP1 expression. Results: Almost half of the patients with cHCC-iCCA were diagnosed with high ACYP1 expression. In all three cohorts, the cases with high ACYP1 expression had significantly lower overall survival, and high ACYP1 expression was identified as an independent prognostic factor. Downregulation of ACYP1 reduced the proliferative capacity, migration, and invasiveness of both HCC and iCCA cells. Moreover, knockdown of ACYP1 increased the ratio of apoptotic cells and decreased the expression of anti-apoptosis proteins. In vivo tumor growth was significantly inhibited by the transfection of ACYP1 siRNA, and the number of apoptotic cells increased. Conclusion: High ACYP1 expression could influence the prognosis of cHCC-iCCA, HCC, and iCCA patients. In vitro ACYP1 expression influences the tumor growth and cell viability in both HCC and iCCA by regulating anti-apoptosis proteins.

DOI： 10.1007/s10620-021-07266-x

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Language：English   Publisher：Proceedings of the National Academy of Sciences of the United States of America  

Breast cancer is the most frequent malignancy in women worldwide. Basal-like breast cancer (BLBC) is the most aggressive form of this disease, and patients have a poor prognosis. Here, we present data suggesting that the Hippo-transcriptional coactivator with PDZ-binding motif (TAZ) pathway is a key driver of BLBC onset and progression. Deletion of Mob1a/b in mouse mammary luminal epithelium induced rapid and highly reproducible mammary tumorigenesis that was dependent on TAZ but not yes-associated protein 1 (YAP1). In situ early-stage BLBC-like malignancies developed in mutant animals by 2 wk of age, and invasive BLBC appeared by 4 wk. In a human estrogen receptor+ luminal breast cancer cell line, TAZ hyperactivation skewed the features of these luminal cells to the basal phenotype, consistent with the aberrant TAZ activation frequently observed in human precancerous BLBC lesions. TP53 mutation is rare in human precancerous BLBC but frequent in invasive BLBC. Addition of Trp53 deficiency to our Mob1a/b-deficient mouse model enhanced tumor grade and accelerated cancer progression. Our work justifies targeting the Hippo-TAZ pathway as a therapy for human BLBC, and our mouse model represents a powerful tool for evaluating candidate agents.

DOI： 10.1073/pnas.2123134119

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Language：English   Publisher：Japanese Society of Interventional Radiology  

<p>In response to the recommendation by the International Commission on Radiological Protection to lower the equivalent eye dose limit, the Japanese Government in April 2021 lowered the equivalent dose limit for the eye lens for occupational exposure. A considerable number of interventional radiology operators are exposed to levels above the new limit. For this reason, a need exists to more accurately evaluate eye lens dose in interventional radiology operators by using a novel direct eye dosimeter, the DOSIRIS™ (IRSN, France), which is capable of measuring a 3-mm dose equivalent under protective glasses. The DOSIRIS is a thermoluminescent dosimeter that exhibits good energy dependence and better directional properties than other dosimeters. Dosimetry using DOSIRIS might be accurate and compatible with the latest regulations.</p>

DOI： 10.22575/interventionalradiology.2022-0005

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CiNii Research

Language：English   Publishing type：Research paper (scientific journal)  

DOI： doi: 10.1158/0008-5472.CAN-21-0653.

Language：English   Publisher：Scientific Reports  

Breast-conserving surgery has become the preferred treatment method for breast cancer. Surgical margin assessment is performed during surgery, as it can reduce local recurrence in the preserved breast. Development of reliable and lower-cost ex vivo cancer detection methods would offer several benefits for patient care. Here, a practical and quantitative evaluation method for the ex vivo fluorescent diagnosis of breast lesions was developed and confirmed through a three-step clinical study. Gamma-glutamyl-hydroxymethyl rhodamine green (gGlu-HMRG) has been reported to generate fluorescence in breast lesions. Using this probe, we constructed a reliable and reproducible procedure for the quantitative evaluation of fluorescence levels. We evaluated the reliability of the method by considering reproducibility, temperature sensitivity, and the effects of other clinicopathological factors. The results suggest that the fluorescence increase of gGlu-HMRG is a good indicator of the malignancy of breast lesions. However, the distributions overlapped. A 5 min reaction with this probe could be used to distinguish at least part of the normal breast tissue. This method did not affect the final pathological examination. In summary, our results indicate that the methods developed in this study may serve as a feasible intraoperative negative-margin assessment tool during breast-conserving surgery.

DOI： 10.1038/s41598-022-12614-6

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DOI： doi: 10.1038/s41417-021-00401-w.

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DOI： doi: 10.1038/s41598-022-12614-6.

Language：English   Publisher：Cancer Gene Therapy  

The accurate and early diagnosis and classification of cancer origin from either tissue or liquid biopsy is crucial for selecting the appropriate treatment and reducing cancer-related mortality. Here, we established the CAncer Cell-of-Origin (CACO) methylation panel using the methylation data of the 28 types of cancer in The Cancer Genome Atlas (7950 patients and 707 normal controls) as well as healthy whole blood samples (95 subjects). We showed that the CACO methylation panel had high diagnostic potential with high sensitivity and specificity in the discovery (maximum AUC = 0.998) and validation (maximum AUC = 1.000) cohorts. Moreover, we confirmed that the CACO methylation panel could identify the cancer cell type of origin using the methylation profile from liquid as well as tissue biopsy, including primary, metastatic, and multiregional cancer samples and cancer of unknown primary, independent of the methylation analysis platform and specimen preparation method. Together, the CACO methylation panel can be a powerful tool for the classification and diagnosis of cancer.

DOI： 10.1038/s41417-021-00401-w

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Language：English   Publisher：Patterns  

Drug repurposing using artificial intelligence algorithms is a powerful technique that leverages existing datasets to find new medical applications for approved drugs. Pham et al. developed CIGER, a deep learning framework to overcome unreliable data in the datasets and present repositioned drugs against pancreatic cancer.

DOI： 10.1016/j.patter.2022.100470

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DOI： doi: 10.1016/j.patter.2022.100470.

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Web of Science

Web of Science

Language：English   Publisher：ONCOLOGY (United States)  

Introduction: Fanconi anemia complementation group E (FANCE) is a Fanconi anemia (FA) pathway gene that regulates DNA repair. We evaluated the clinical relevance of FANCE expression in hepatocellular carcinoma (HCC). Methods: First, the associations between the expression of FA pathway genes including FANCE and clinical outcomes in HCC patients were analyzed in 2 independent cohorts: The Cancer Genome Atlas (TCGA, n = 373) and our patient cohort (n = 53). Localization of FANCE expression in HCC tissues was observed by immunohistochemical staining. Gene set enrichment analysis (GSEA) and gene network analysis (SiGN_BN) were conducted using the TCGA dataset. Next, an in vitro proliferation assay was performed using FANCE-knockdown HCC cell lines (HuH7 and HepG2). The association between mRNA expression of FANCE and that of DNA damage response genes in HCC was analyzed using TCGA and Cancer Cell Line Encyclopedia datasets. Finally, the association between FANCE mRNA expression and overall survival (OS) in various digestive carcinomas was analyzed using TCGA data. Results: FANCE was highly expressed in HCC cells. Multivariate analysis indicated that high FANCE mRNA expression was an independent factor predicting poor OS. GSEA revealed a positive relationship between enhanced FANCE expression and E2F and MYC target gene expression in HCC tissues. FANCE knockdown attenuated the proliferation of HCC cells, as well as reduced cdc25A expression and elevated histone H3 pSer10 expression. SiGN_BN revealed that FANCE mRNA expression was positively correlated with DNA damage response genes (H2A histone family member X and checkpoint kinase 1) in HCC tissues. Significant effects of high FANCE expression on OS were observed in hepatobiliary pancreatic carcinomas, including HCC. Conclusions: FANCE may provide a potential therapeutic target and biomarker of poor prognosis in HCC, possibly by facilitating tumor proliferation, which is mediated partly by cell cycle signaling activation.

DOI： 10.1159/000520582

Web of Science

Scopus

PubMed

Web of Science

Web of Science

Language：Japanese   Publisher：(公財)鈴木謙三記念医科学応用研究財団  

Language：English   Publishing type：Research paper (scientific journal)  

DOI： doi: 10.1016/j.biomaterials.2021.121256.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： doi: 10.1111/cas.15174.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： doi: 10.1159/000520582.

Language：English   Publisher：Cancer Science  

Colorectal cancer (CRC) is one of the most common types of cancer and a significant cause of cancer mortality worldwide. Further improvements of CRC therapeutic approaches are needed. BCL2-associated athanogene 6 (BAG6), a multifunctional scaffold protein, plays an important role in tumor progression. However, regulation of BAG6 in malignancies remains unclear. This study showed that guided entry of tail-anchored proteins factor 4 (GET4), a component of the BAG6 complex, regulates the intercellular localization of BAG6 in CRC. Furthermore, GET4 was identified as a candidate driver gene on the short arm of chromosome 7, which is often amplified in CRC, by our bioinformatics approach using the CRC dataset from The Cancer Genome Atlas. Clinicopathologic and prognostic analyses using CRC datasets showed that GET4 was overexpressed in tumor cells due to an increased DNA copy number. High GET4 expression was an independent poor prognostic factor in CRC, whereas BAG6 was mainly overexpressed in the cytoplasm of tumor cells without gene alteration. The biological significance of GET4 was examined using GET4 KO CRC cells generated with CRISPR-Cas9 technology or transfected CRC cells. In vitro and in vivo analyses showed that GET4 promoted tumor growth. It appears to facilitate cell cycle progression by cytoplasmic enrichment of BAG6-mediated p53 acetylation followed by reduced p21 expression. In conclusion, we showed that GET4 is a novel driver gene and a prognostic biomarker that promotes CRC progression by inducing the cytoplasmic transport of BAG6. GET4 could be a promising therapeutic molecular target in CRC.

DOI： 10.1111/cas.15174

Web of Science

Scopus

PubMed

Language：English   Publisher：Biomaterials  

Recent genetic studies have indicated relationships between gene mutations and colon cancer phenotypes. However, how physical properties of tumor cells are changed by genetic alterations has not been elucidated. We examined genotype-defined mouse intestinal tumor-derived cells using a high-speed scanning ion conductance microscope (HS-SICM) that can obtain high-resolution live images of nano-scale topography and stiffness. The tumor cells used in this study carried mutations in Apc (A), Kras (K), Tgfbr2 (T), Trp53 (P), and Fbxw7 (F) in various combinations. Notably, high-metastatic cancer-derived cells carrying AKT mutations (AKT, AKTP, and AKTPF) showed specific ridge-like morphology with active membrane volume change, which was not found in low-metastatic and adenoma-derived cells. Furthermore, the membrane was significantly softer in the metastatic AKT-type cancer cells than other genotype cells. Importantly, a principal component analysis using RNAseq data showed similar distributions of expression profiles and physical properties, indicating a link between genetic alterations and physical properties. Finally, the malignant cell-specific physical properties were confirmed by an HS-SICM using human colon cancer-derived cells. These results indicate that the HS-SICM analysis is useful as a novel diagnostic strategy for predicting the metastatic ability of cancer cells.

DOI： 10.1016/j.biomaterials.2021.121256

Scopus

PubMed

Language：English   Publisher：John Wiley & Sons Australia, Ltd  

BCL2関連athanogene 6(BAG6)複合体の構成要素であるguided entry of tail-anchored proteins factor 4(GET4)が、大腸癌においてBAG6の細胞内局在を制御していることを明らかにした。癌ゲノムデータベースのデータセットを解析したところ、大腸癌でGET4遺伝子はしばしば増幅しており、ドライバー遺伝子の候補となることが突き止められた。GET4遺伝子は腫瘍細胞でDNAコピー数が増加しているために過剰発現していることが判明し、GET4高発現は予後不良の独立因子となっていた。BAG6には遺伝子変化が認められ、主に腫瘍細胞の細胞質内で過剰発現していた。大腸癌細胞を用いたノックアウト実験によってGET4の生物学的重要性について検討した。その結果、in vitro、in vivoのいずれでもGET4は腫瘍の増殖を促進することが示された。BAG6が媒介するp53のアセチル化が細胞質内で豊富に生じ、次いでp21発現が減少するために細胞周期の進行が促進されていると思われた。以上から、GET4はBAG6の細胞質移行を誘導して大腸癌の進行を促進する新規ドライバー遺伝子であり、予後バイオマーカーにもなることが明らかになった。

Language：Japanese   Publisher：Japanese Society for Molecular Tumor Marker Research  

DOI： 10.11241/jsmtmr.38.24

CiNii Research

Language：Japanese   Publisher：The Japan Society of Coloproctology  

<p>Since the start of genome medicine in 2019, patients with colorectal cancer and other types of cancer who have been treated with molecular targeted drugs have shown prolonged survival. Recently, we were astounded by the efficacy of the clinical trial of Dostralimab, a PD-1 blockade agent which showed complete response in 12 (100%) out of 12 rectal cancer cases harboring deficient MMR genes. Colorectal cancer has critical genomic alterations in the WNT signaling pathway, including APC/β catenin, EGFR/PI3K signaling pathway including KRAS, notch signaling pathway, and TGFβ signaling pathway, and drug discovery targeting these pathways is being conducted worldwide. In general, it is challenging to develop inhibitors for nuclear transcription factors. This review article focuses on the colorectal cancer therapies that target these genetic mutations, including immunotherapy, and presents some relevant information on therapeutics.</p>

DOI： 10.3862/jcoloproctology.75.449

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)  

DOI： doi: 10.1007/s10620-021-07266-x.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： doi: 10.1007/s00595-021-02273-x.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： doi: 10.1111/cas.15022.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： doi: 10.1159/000517854.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： doi: 10.1186/s12915-021-01147-5.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： doi: 10.1371/journal.pone.0256471.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： doi: 10.1038/s41598-021-98485-9.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： doi: 10.21873/cgp.20277.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/cas.14969.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1371/journal.pone.0241140.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.18632/oncotarget.27852.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s10038-021-00930-0.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1002/cam4.3828.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/cas.14858.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s00595-021-02273-x.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： doi: 10.1371/journal.pgen.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1371/journal.pgen.1009113.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.14309/ctg.0000000000000269.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1053/j.gastro.2020.08.018.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/tbj.14108

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1158/0008-5472.CAN-18-3544.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/cas.14581.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.21873/anticanres.14362.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/cas.14515.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.21873/anticanres.14272.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1159/000506075.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/cas.14318.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.7717/peerj.8842.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1245/s10434-020-08375-z.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1126/sciadv.aay3324.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.21873/cgp.20174.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/cas.14248.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/cas.14306.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3390/ijms21020511.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1245/s10434-018-7056-7.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/cas.14163.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41467-019-11826-1.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.ebiom.

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41598-017-18488-3.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/cas.13968.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/cas.14075.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/cas.14075.

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/cas.13968.

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s00595-019-01789-7.

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.3892/ol.2018.9819.

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41586-018-0811-x.

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.21873/cgp.20109.

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.21873/anticanres.13084.

Language：English   Publishing type：Research paper (scientific journal)  

Although body-warming with hot spa-bathing has been proposed to exert medical therapeutic effects on certain diseases, whether body-warming has preventive and promotive effects remains unknown. To clarify this issue, an epidemiological questionnaire study regarding personal hot spa-bathing habits and disease history was carried out in Japan, where individuals engage in daily warm water bathing. Questionnaires regarding hot spa-bathing habits and disease history were randomly sent to 20,000 residents aged ≥65 years living in Beppu, a city in Japan that has the highest concentration of hot spa sources in the world. The results showed that habitual hot spa-bathing exerts preventive or promotive effects on the occurrence of certain diseases, such as hypertension (preventive) and collagen disease (promotive) in women, and cardiovascular diseases (preventive) and colon cancer survival (promotive) in men. These findings suggest that habitual body warming is an effective and economical method with beneficial preventive and promotive effects on various diseases.

DOI： 10.1038/s41598-017-18488-3

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.21873/anticanres.13030.

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.1245/s10434-018-6739-4.

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41416-018-0208-5.

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.21873/anticanres.12755.

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.1002/ags3.12182.

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.21873/cgp.20089.

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41467-018-05226-0.

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.1093/carcin/bgy026.

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/cas.13510.

Language：English   Publishing type：Research paper (scientific journal)  

Cancer is composed of multiple cell populations with different genomes. This phenomenon called intratumor heterogeneity (ITH) is supposed to be a fundamental cause of therapeutic failure. Therefore, its principle-level understanding is a clinically important issue. To achieve this goal, an interdisciplinary approach combining genome analysis and mathematical modeling is essential. For example, we have recently performed multiregion sequencing to unveil extensive ITH in colorectal cancer. Moreover, by employing mathematical modeling of cancer evolution, we demonstrated that it is possible that this ITH is generated by neutral evolution. In this review, we introduce recent advances in a research field related to ITH and also discuss strategies for exploiting novel findings on ITH in a clinical setting.

DOI： 10.1111/cas.13510

Language：English   Publishing type：Research paper (scientific journal)  

Colorectal cancer is driven by the accumulation of driver mutations, but the contributions of specific mutations to different steps in malignant progression are not fully understood. In this study, we generated mouse models harboring different combinations of key colorectal cancer driver mutations (Apc, Kras, Tgfbr2, Trp53, Fbxw7) in intestinal epithelial cells to comprehensively investigate their roles in the development of primary tumors and metastases. Apc^δ716 mutation caused intestinal adenomas and combination with Trp53^R270 mutation or Tgfbr2 deletion induced submucosal invasion. The addition of Kras^G12D mutation yielded epithelial-mesenchymal transition (EMT)-like morphology and lymph vessel intravasation of the invasive tumors. In contrast, combinations of Apc^δ716 with Kras^G12D and Fbxw7 mutation were insufficient for submucosal invasion, but still induced EMT-like histology. Studies using tumor-derived organoids showed that Kras^G12D was critical for liver metastasis following splenic transplantation, when this mutation was combined with either Apc^δ716 plus Trp53^R270H or Tgfbr2 deletion, with the highest incidence of metastasis displayed by tumors with a Apc^δ716 Kras^G12D Tgfbr2^-/- genotype. RNA sequencing analysis of tumor organoids defined distinct gene expression profiles characteristic for the respective combinations of driver mutations, with upre-gulated genes in Apc^δ716 Kras^G12D Tgfbr2^-/- tumors found to be similarly upregulated in specimens of human metastatic colorectal cancer. Our results show how activation of Wnt and Kras with suppression of TGFβ signaling in intestinal epithelial cells is sufficient for colorectal cancer metastasis, with possible implications for the development of metastasis prevention strategies.

DOI： 10.1158/0008-5472.CAN-17-3303

Language：English   Publishing type：Research paper (scientific journal)  

Background: In gastric cancer (GC), peritoneal dissemination (PD) occurs frequently and is incurable. In this study, we aimed to identify PD-associated genes in GC. Methods: We identified a PD-associated gene using three GC datasets: highly disseminated peritoneal GC cell lines, the Singapore dataset and The Cancer Genome Atlas (TCGA) dataset. We assessed the clinicopathological significance of the gene expression using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and performed immunohistochemical analysis for the gene in our patient cohort. We also performed survival analyses of the gene in our patient cohort, the Singapore dataset and the GSE62254 datasets. Moreover, gene set enrichment analysis (GSEA) was performed using the Singapore and TCGA datasets. Finally, in vitro experiments such as invasion/migration assays, immunofluorescence staining of actin filaments, epidermal growth factor (EGF) treatment analysis, and gene expression analysis were conducted using three gene-knockdown GC cell lines (AGS, 58As9, MKN45). Results: ADP-ribosylation factor-like 4c (ARL4C) was identified as a PD-associated gene, and immunohistochemical analysis showed that ARL4C was overexpressed in GC cells. High ARL4C expression was associated with the depth of invasion (p < 0.01) and PD (p < 0.05) and was a poor prognostic factor (p < 0.05) in our patient cohort, the Singapore dataset and the GSE62254 dataset. ARL4C expression positively correlated with the epithelial–mesenchymal transition (EMT) gene set in GSEA. Moreover, ARL4C knockdown reduced invasion/migration capacity, SLUG expression, and the formation of lamellipodia or filopodia in AGS and 58As9 cells. Finally, EGF treatment increased ARL4C expression in MKN45 cells. Conclusions: ARL4C was associated with PD and was a poor prognostic factor in GC, possibly through promoting invasive capacity by activation of both EMT and motility.

DOI： 10.1245/s10434-017-6292-6

Language：English   Publishing type：Research paper (scientific journal)  

Peritoneal dissemination is the most common metastatic pattern in advanced gastric cancer (GC) and has a very poor prognosis. However, its molecular mechanism has not been elucidated. Our study investigated genes associated with peritoneal dissemination of GC. We performed combined expression analysis of metastatic GC cell lines and identified Procollagen-lysine, 2-oxoglutarate 5-dioxygenase2 (PLOD2) as a potential regulator of peritoneal dissemination. PLOD2 is regulated by hypoxia-inducible factor-1 (HIF-1) and mediates extracellular matrix remodeling, alignment, and mechanical properties. We analyzed PLOD2 expression immunohistochemically in 179 clinical samples, and found high PLOD2 expression to be significantly associated with peritoneal dissemination, leading to poor prognosis. In an in vivo-collected metastatic cell line, downregulation of PLOD2 by siRNA reduced invasiveness and migration. Hypoxia upregulated PLOD2 mediated by HIF-1, and promoted invasiveness and migration. After exposure to hypoxia, a cell line transfected with siPLOD2 exhibited significantly suppressed invasiveness and migration, despite high HIF-1 expression. These findings indicate that PLOD2 is a regulator of, and candidate therapeutic target for peritoneal dissemination of GC. Although peritoneal dissemination of GC has a very poor prognosis, its molecular mechanism has not been elucidated. We identified PLOD2 regulated by HIF-1 as a potential regulator of peritoneal dissemination of GC. Finally, we showed that PLOD2 promotes cell invasiveness and migration in GC under hypoxia and lead to peritoneal dissemination of GC.

DOI： 10.1002/ijc.31410

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.3892/mco.2017.1502.

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.1159/000488860.

Language：English   Publishing type：Research paper (scientific journal)  

Purpose: More effective methods are needed for breast reconstruction after breast-conserving surgery for breast cancer. The aim of this clinical study was to assess the perioperative and long-term outcomes of adipose-derived regenerative cell (ADRC)-enriched autologous fat grafting. Methods: Ten female patients who had undergone breast-conserving surgery and adjuvant radiotherapy for breast cancer were enrolled. An ADRC-enriched fat graft prepared from the patient’s adipose tissue was implanted at the time of adipose tissue harvest. The perioperative and long-term outcomes of the grafts, which included safety, efficacy, and questionnaire-based patient satisfaction, were investigated. Results: The mean operation time was 188 ± 30 min, and the mean duration of postoperative hospitalization was 1.2 ± 0.4 days. No serious postoperative complications were associated with the procedure. Neither recurrence nor metastatic disease was observed during the follow-up period (7.8 ± 1.5 years) after transplantation. Of 9 available patients, “more than or equal to average” satisfaction with breast appearance and overall satisfaction were reported by 6 (66.7%) and 5 (55.6%) patients, respectively. Conclusions: ADRC-enriched autologous fat transplantation is thus considered to be safe perioperatively, with no long-term recurrence, for patients with breast cancer treated by breast-conserving surgery, and it may be an option for breast reconstruction, even after adjuvant radiotherapy.

DOI： 10.1007/s00595-017-1544-4

Language：English   Publishing type：Research paper (scientific journal)  

Background: Recently, several immune checkpoint inhibitors have been developed and are being used to treat malignant melanoma, lung cancer, and other cancers. Several reports have indicated that tumor-infiltrating lymphocytes (TILs) are associated with clinical and histopathologic risk factors in various cancers. However, the role of TILs in esophageal squamous cell carcinoma (ESCC) has not been well studied. This study aimed to investigate the perilesional status of TILs in ESCC and to show associations between TILs and clinical variables. Methods: The study enrolled 277 ESCC patients. Evaluation of TILs was performed according to the criteria of the International TILs Working Group 2014, and associations between TIL and clinicopathologic variables were examined. Results: Most of the clinicopathologic factors were not statistically associated with TIL status. The number of patients who received adjuvant therapy was significantly larger in the TIL-negative group. Cancer-specific survival (CSS) of patients in the TIL-positive group was significantly better than in the TIL-negative group. Among the patients who received adjuvant therapy, CSS was significantly better in the TIL-positive group than in the TIL-negative group. Uni- and multivariate analyses identified tumor depth and TIL status as independent prognostic factors for CSS. Among the other clinicopathologic variables, TIL status was the strongest CSS indicator. Conclusion: Tumor-infiltrating lymphocyte status is a strong predictor of good prognosis for ESCC patients.

DOI： 10.1245/s10434-017-5796-4

Language：English   Publishing type：Research paper (scientific journal)  

Genome-wide association studies are a powerful tool for searching for disease susceptibility loci. Several studies identifying single nucleotide polymorphisms (SNP) connected intimately to the onset of colorectal cancer (CRC) have been published, but there are few reports of genome-wide association studies in Japan. To identify genetic variants that modify the risk of CRC oncogenesis, especially in the Japanese population, we performed a multi-stage genome-wide association study using a large number of samples: 1846 CRC cases and 2675 controls. We identified 4 SNP (rs7912831, rs4749812, rs7898455 and rs10905453) in chromosome region 10p14 associated with CRC; however, there are no coding or non-coding genes within this region of fairly extensive linkage disequilibrium (a 500-kb block) on 10p14. Our study revealed that the 10p14 locus is significantly correlated with susceptibility to CRC in the Japanese population, in accordance with the results of multiple studies in other races.

DOI： 10.1111/cas.13391

Language：English   Publishing type：Research paper (scientific journal)  

Introduction Pneumatosis intestinalis is rare but may be associated with life-threatening intra-abdominal conditions such as intestinal ischemia or perforation. However, it can be difficult, particularly in the very elderly, to identify candidates for immediate surgical intervention. Presentation of case A 94-year-old man with abdominal distension underwent abdominal computed tomography, which demonstrated accumulation of air bubbles within the intestinal wall and some free intraperitoneal air, suggestive of pneumatosis intestinalis. His vital signs showed evidence of systemic inflammatory response syndrome, and laboratory examination revealed inflammation and hypoxia. As the patient was frail, with his age and concomitant conditions which may have masked the symptoms and severity of his illness, immediate diagnostic laparoscopy was performed, which confirmed the diagnosis of pneumatosis intestinalis, with multiple gas-filled cysts seen within the subserosa of the small intestine. No additional surgical procedure was performed. His symptoms improved postoperatively. Discussion Optimal management of pneumatosis intestinalis in a timely manner requires a comprehensive evaluation of factors in each individual. In patients with severe symptoms, PI might be a sign of a life-threatening intra-abdominal emergency. Despite the contrast-enhanced CT and prediction markers in previous reports, it considered to be difficult to completely rule out these fatal conditions without surgery, especially in very elderly patients with poor performance status. Conclusion Diagnostic laparoscopy may be a useful option for definitively ruling out the lethal conditions associated with pneumatosis intestinalis in frail elderly patients with severe conditions in the emergency setting.

DOI： 10.1016/j.amsu.2017.07.058

Language：English   Publishing type：Research paper (scientific journal)  

MicroRNAs (miRs) are small RNAs that repress mRNA translation, resulting in the degradation of mRNAs and regulation of the expression levels of various genes. Recent studies have shown that aberrant miR expression has a functional role in the initiation and progression of various malignancies, including colorectal cancer (CRC), which is one of the leading causes of cancer-related death worldwide. miRs have also been shown to have applications as diagnostic, prognostic, and predictive biomarkers because of their high tissue specificity, stability, and altered expression in tumor development. In this report, we examined the role of miRs as biomarkers in CRC through a review of meta-analyses and large-scale analyses having strong statistical confidence in the study outcomes. We also discuss current issues in the clinical application of these miRs.

DOI： 10.3390/cancers9090124

Language：English   Publishing type：Research paper (scientific journal)  

Objective: MOB1, a core component of the Hippo signaling pathway, suppresses cell proliferation, and MOB1 liver conditional knockout mice develop intrahepatic cholangiocarcinoma (ICC). However, its clinical significance in human ICC has not been established. The aim of this study was to characterize protein levels and the role of Hippo and TGF pathways in ICCs. Methods: The protein levels of yes-associated protein 1 (YAP1), MOB1, Smad2, and TGFβ2 in 88 ICC cases were analyzed. Protein level was graded by a scoring system; then, the clinicopathological factors, including prognosis, were analyzed based on protein level. Results: Nuclear overexpression of YAP1 was seen in 28 cases (31.8%), and it was significantly associated with a poor overall survival rate (p = 0.01). MOB1 expression decreased in 42 cases (47.7%) and was associated with a poor overall survival rate (p = 0.02). SMAD2 nuclear localization was significantly correlated with a high YAP1 level independent of TGFβ2. Multivariate analysis revealed that a high YAP1 level, a low MOB1 level, and lymphatic permeation were independent risk factors for overall survival. Conclusions: These results showed that key components of the Hippo signaling pathway are aberrantly expressed and associated with the malignant potential of human ICC.

DOI： 10.1159/000463390

Language：English   Publishing type：Research paper (scientific journal)  

Background: Among several candidate genes that promote peritoneal dissemination extracted by comprehensive expression analysis of both in vivo selected metastatic cell lines and patients with gastric cancer, we focused on the chemokine (C-X-C motif) receptor (CXCR7) and explored its clinicopathological significance in gastric cancer. Methods:CXCR7 expression was evaluated by microarray data in the Singapore cohort (n = 196) and by immunohistochemistry and reverse transcription quantitative real-time polymerase chain reaction in the Japanese cohort (n = 195). The biological function of CXCR7 in gastric cancer was explored using gene set enrichment analysis (GSEA). Results: CXCR7 expression was upregulated in tumor tissues compared to normal tissues. High CXCR7 mRNA expression was associated with peritoneal dissemination and poor prognosis in the Singapore cohort. Consistent with this, the high CXCR7 mRNA expression group showed significantly poorer prognosis and a more aggressive disease course than the low expression group in the Japanese cohort. High CXCR7 mRNA expression and peritoneal dissemination were clinically relevant. GSEA revealed that CXCR7 was significantly enriched in gene expression signatures associated with tumor progression. Conclusions:CXCR7 may be a prognostic indicator and therapeutic target for gastric cancer with peritoneal dissemination.

DOI： 10.1159/000452977

Language：English   Publishing type：Research paper (scientific journal)  

Mps One Binder Kinase Activator (MOB)1A/1B are core components of the Hippo pathway. These proteins, which coactivate LArge Tumour Suppressor homologue kinases, are also tumour suppressors. To investigate MOB1A/B's roles in normal physiology and lung cancer, we generated doxycycline (Dox)-inducible, bronchioalveolar epithelium-specific, null mutations of MOB1A/B in mice (SPC-rtTA/(tetO) 7-Cre/Mob1a ^flox/flox/Mob1b^-/- termed luMob1DKO mice). Most mutants (70%) receiving Dox in utero (luMob1DKO (E6.5-18.5) mice) died of hypoxia within 1 h post-birth. Their alveolar epithelial cells showed increased proliferation, impaired YAP1/TAZ-dependent differentiation and decreased surfactant protein production, all features characteristic of human respiratory distress syndrome. Intriguingly, mutant mice that received Dox postnatally (luMob1DKO (P21-41) mice) did not develop spontaneous lung adenocarcinomas, and urethane treatment-induced lung tumour formation was decreased (rather than increased). Lungs of luMob1DKO (P21-41) mice exhibited increased detachment of bronchiolar epithelial cells and decreased numbers of the bronchioalveolar stem cells thought to initiate lung adenocarcinomas. YAP1/TAZ-NKX2.1-dependent expression of collagen XVII, a key hemidesmosome component, was also reduced. Thus, a MOB1-YAP1/TAZ-NKX2.1 axis is essential for normal lung homeostasis and expression of the collagen XVII protein necessary for alveolar stem cell maintenance in the lung niche.

DOI： 10.1038/onc.2017.58

Language：English   Publishing type：Research paper (scientific journal)  

DNA analysis is used for a variety of purposes, including disease diagnosis and DNA profiling; this involves extracting DNA from living organisms. In this study, we prepared polycationic silica particles to extract DNA that has the negatively charged phosphate backbone from solution. The coated particles were prepared by mixing conventional silica gel particles and poly-Lys; these particles could efficiently extract 1.3 μg of cell-free DNA from 50 mL of (male) urine. It is expected that these easily prepared particles (just a mixture of two commercially available chemicals) can be used as a noninvasive diagnostic tool for genetic disorders such as cancer, diabetes, and hypertension. [Figure not available: see fulltext.].

DOI： 10.1007/s00216-017-0345-3

Language：English   Publishing type：Research paper (scientific journal)  

Background: We previously identified discoidindomain receptor 2 (DDR2) as a promising driver gene of peritoneal dissemination (PD) in gastric cancer. In the present study we explored the clinical significance of DDR2 expression in colorectal cancer (CRC). Materials and Methods: We examined DDR2 expression in CRC specimens by immunohistochemistry. We analyzed the association of DDR2 expression with clinicopathological factors in CRC. We divided 63 CRC cases into two groups according to their level of DDR2 expression and compared several clinicopathological factors and their overall survival. Results: The group with high DDR2 expression had significantly higher frequencies of T4, lymph node metastasis, and PD compared to the group with low DDR2 expression. Furthermore, the prognosis of the group with high DDR2 expression was significantly poorer than the group with low DDR2. Conclusion: DDR2 is a powerful biomarker that can predict poor prognosis as well as PD, and might be an effective therapeutic target for CRC.

DOI： 10.21873/anticanres.11603

Language：English   Publishing type：Research paper (scientific journal)  

Multi-regional sequencing provides new opportunities to investigate genetic heterogeneity within or between common tumors from an evolutionary perspective. Several state-of-the-art methods have been proposed for reconstructing cancer evolutionary trees based on multi-regional sequencing data to develop models of cancer evolution. However, there have been few studies on comparisons of a set of cancer evolutionary trees. We propose a clustering method (phyC) for cancer evolutionary trees, in which sub-groups of the trees are identified based on topology and edge length attributes. For interpretation, we also propose a method for evaluating the sub-clonal diversity of trees in the clusters, which provides insight into the acceleration of sub-clonal expansion. Simulation showed that the proposed method can detect true clusters with sufficient accuracy. Application of the method to actual multi-regional sequencing data of clear cell renal carcinoma and non-small cell lung cancer allowed for the detection of clusters related to cancer type or phenotype. phyC is implemented with R(≥3.2.2) and is available from https://github.com/ymatts/phyC.

DOI： 10.1371/journal.pcbi.1005509

Language：English   Publishing type：Research paper (scientific journal)  

Background/Aim: SLC9A9 plays an oncogenic role in esophageal squamous carcinoma and glioblastoma. Herein, we showed an oncogenic function of SLC9A9 in colorectal cancer (CRC). Materials and Methods: We examined SLC9A9 expression in CRC specimens by immunohistochemistry. In CRC tissues, the relationship between SLC9A9 expression and clinicopathological factors was further elucidated by quantitative real-time polymerase chain reaction (qRT-PCR) and gene set enrichment analysis (GSEA). In vitro, we performed knockdown and overexpression experiments. Results: SLC9A9 was overexpressed in CRC specimens. In clinicopathological analysis of our cohort, high SLC9A9 expression increased liver metastasis and was correlated with worse prognoses in two cohorts. A significantly positive relationship between SLC9A9 and EGFR was revealed. While knockdown of SLC9A9 suppressed proliferation and anchorageindependent growth, up-regulation of SLC9A9 promoted proliferation and anchorage-independent growth in vitro. Conclusion: SLC9A9 has an oncogenic function by being related to EGFR signaling, suggesting SLC9A9 may be a novel prognostic indicator and a therapeutic target in CRC.

DOI： 10.21873/anticanres.11562

Language：English   Publishing type：Research paper (scientific journal)  

Background/Aim: Amplification of chromosome 7p (Ch.7p) is common in colorectal cancer (CRC). The aim of this study was to identify potential driver genes on Ch.7p that are overexpressed due to DNA copy number amplification and determine their clinical significance in CRC. Materials and Methods: We identified phosphoserine phosphatase (PSPH) as a potential driver gene using a CRC dataset from The Cancer Genome Atlas (TCGA) using a bioinformatics approach. The expression of PSPH in 124 primary CRCs was examined by quantitative reverse transcription polymerase chain reaction (PCR) and immunohistochemistry. The biological effect of PSPH expression was explored by Gene Set Enrichment Analysis (GSEA) using the TCGA dataset. Results: PSPH was overexpressed in tumor tissues and PSPH positively correlated with depth of invasion and distant metastasis. On multivariate analysis, high PSPH expression was an independent poor prognostic factor. These results were supported by GSEA. Conclusion: PSPH could be a novel prognostic biomarker with malignant potential on Ch.7p in CRC.

DOI： 10.21873/anticanres.11574

Language：English   Publishing type：Research paper (scientific journal)  

MicroRNAs (miRNAs) are small (18-25 nucleotides) noncoding RNA molecules that bind to partially complementary mRNA sequences, resulting in target degradation or translation inhibition. A single miRNA can influence the expression of hundreds of target genes, and miRNAs have been implicated as key molecules in various diseases, including cancer. Many studies have shown that the miRNAs play an important role in cancer cells and tumor microenvironment and may be biomarkers for early detection and therapeutic targets for various cancers. Recently, relationships between miRNAs and immunocheckpoint molecules have been focused on as new tumor progression associated mechanisms. As for biomarkers, cell-free miRNAs detected in body fluids (circulating miRNAs) have attached the attention of researchers due to their potential as tumor-specific and non-invasive biomarkers. In terms of strategies to use miRNAs as therapeutic targets, developments of tissue specific delivery systems, including lipid nanoparticles or exosome vectors, are progressing. Here we will review the mechanisms and clinical uses of miRNAs in cancer.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1245/s10434-016-5573-9.

Language：English   Publishing type：Research paper (scientific journal)  

Background: The RND1 gene encodes a protein that belongs to the Rho GTPase family, which regulates various cellular functions. Depletion of RND1 expression activates the oncogenic Ras signaling pathway. In this study, we aimed to clarify the clinical significance of RND1 expression in predicting prognosis and to investigate its biological role in human hepatocellular carcinoma (HCC). Methods: The association between RND1 expression and clinical outcomes in patients with HCC was analyzed in three independent cohorts: 120 cases resected in our hospital; 370 cases in The Cancer Genome Atlas (TCGA); and 242 cases in GSE14520. Gene set enrichment analysis (GSEA) was also conducted. Finally, knockdown experiments were performed using small interfering RNA (siRNA) in vitro. Results: In all cohorts, RND1 expression was decreased as cancer progressed, and was affected by promoter methylation. In our HCC cases, the 5-year overall survival (OS) and recurrence-free survival of patients with low RND1 expression was significantly poorer than those of patients with high RND1 expression. TCGA and GSE14520 analyses provided similar results for OS. Multivariate analysis indicated that RND1 expression was an independent prognostic factor for OS in all three cohorts. Additionally, GSEA showed an inverse correlation between RND1 expression and the Ras signaling activity. In vitro, knockdown of RND1 expression resulted in significant increases in proliferation, invasion, and chemoresistance to cisplatin in HCC cells. Conclusions: Reduced RND1 expression in HCC was associated with cancer progression, likely through regulation of the Ras signaling pathway, and may serve as a novel clinical biomarker for predicting prognosis in patients with HCC.

DOI： 10.1245/s10434-016-5573-9

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1159/000452977

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1371/journal.pone.0165912

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.18632/oncotarget.11409.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1245/s10434-016-5374-1

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/srep27525.

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1245/s10434-016-5289-x

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1158/0008-5472.CAN-15-2601

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3892/or.2016.4593.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1371/journal.pone.0139808.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3390/jcm4081600.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/bjc.2015.201.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3892/mco.2015.565

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1245/s10434-015-4652-7.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/srep12080.

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND/AIM:

A long noncoding RNA (lncRNA) activated by transforming growth factor (TGF)-β (lncRNA-ATB) was recently described to promote the invasion-metastasis cascade in hepatocellular carcinoma. The aim of the present study was to clarify the clinicopathological role and prognostic relevance of lncRNA-ATB in colorectal cancer (CRC).
MATERIALS AND METHODS:

lncRNA-ATB expression was evaluated by real-time reverse transcription polymerase chain reaction in 124 patients with CRC. Patients were divided into two groups based on the median lncRNA-ATB expression.
RESULTS:

High lncRNA-ATB expression was significantly associated with greater tumor size, depth of tumor invasion, lymphatic invasion, vascular invasion, and lymph node metastasis. Patients of the high-lncRNA-ATB expression group had significantly poorer outcomes than those of the low-expression group. Additionally, levels of lncRNA-ATB expression were significantly higher in patients with hematogenous metastases.
CONCLUSION:

lncRNA-ATB may be involved in the progression of CRC and be a novel indicator of poor prognosis in patients with CRC.

Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.
KEYWORDS:

Long noncoding RNA; TGF-β; colorectal cancer; prognosis; progression

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND:

A recent study reported that long non-coding RNA activated by TGF-β (lncRNA-ATB) induced epithelial-mesenchymal transition (EMT) through the transforming growth factor-β (TGF-β)/miR-200s/ZEB axis in hepatocellular carcinoma. Herein, we focused on the clinical significance of lncRNA-ATB in gastric cancer (GC) patients.
MATERIALS AND METHODS:

Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was performed to examine expression of lncRNA-ATB, miR-200b, and miR-200c in GC tissues (n = 183). Patients were divided into high and low lncRNA-ATB expression groups using a cutoff of lncRNA-ATB/GAPDH ≥0.60 or <0.60 to determine the clinicopathological significance of lncRNA-ATB in GC. Moreover, we evaluated the expression of TGF-β, lncRNA-ATB, miR-200s, and ZEB1 in GC cell lines by qRT-PCR. GC cell lines were treated by recombinant TGF-β1 or TGF-β receptor inhibitor to examine morphologic changes and genetic alterations, such as lncRNA-ATB, miR-200s, and ZEB1 levels, with respect to the EMT phenotype.
RESULTS:

The high lncRNA-ATB group experienced a lower overall survival rate compared with the low lncRNA-ATB group, and multivariate analysis indicated that lncRNA-ATB was an independent prognostic factor (hazard ratio 3.50; 95 % CI 1.73-7.44; p = 0.0004). miR-200c levels were lower and ZEB1 levels were higher in the high lncRNA-ATB group than in the low lncRNA-ATB group. Treatment with TGF-β in GC cell lines resulted in morphological EMT changes, upregulation of lncRNA-ATB and ZEB1, and downregulation of miR-200c and CDH1. SB431542 reduced lncRNA-ATB expression.
CONCLUSION:

LncRNA-ATB plays an important role in EMT to promote invasion and metastasis through the TGF-β/miR-200s/ZEB axis, resulting in a poor prognosis in GC. LncRNA-ATB is a novel biomarker of lncRNA, indicative of a poor prognosis in GC patients.

DOI： 10.1245/s10434-015-4554-8

Language：English   Publishing type：Research paper (scientific journal)  

Polypyrimidine tract-binding protein (PTBP1) is an RNA-binding protein with various molecular functions related to RNA metabolism and a major repressive regulator of alternative splicing, causing exon skipping in numerous alternatively spliced pre-mRNAs. Here, we have investigated the role of PTBP1 in colorectal cancer. PTBP1 expression levels were significantly overexpressed in cancerous tissues compared with corresponding normal mucosal tissues. We also observed that PTBP1 expression levels, c-MYC expression levels, and PKM2:PKM1 ratio were positively correlated in colorectal cancer specimens. Moreover, PTBP1 expression levels were positively correlated to poor prognosis and lymph node metastasis. In analyses of colorectal cancer cells using siRNA for PTBP1, we observed that PTBP1 affects cell invasion, which was partially correlated to CD44 splicing, and this correlation was also confirmed in clinical samples. PTBP1 expression also affected anchorage-independent growth in colorectal cancer cell lines. PTBP1 expression also affected cell proliferation. Using time-lapse imaging analysis, PTBP1 was implicated in prolonged G2-M phase in HCT116 cells. As for the mechanism of prolonged G2-M phase in HCT116 siPTBP1 cells, Western blotting revealed that PTBP1 expression level was correlated to CDK11p58 expression level, which was reported to play an important role on progression to complete mitosis. These findings indicated that PTBP1 is a potential therapeutic target for colorectal cancer. Mol Cancer Ther; 14(7); 1-12. ©2015 AACR.

DOI： 10.1158/1535-7163

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND:

MicroRNAs have roles in the regulation of the epithelial-mesenchymal transition (EMT). Findings have shown that miR-506 inhibits the expression of SNAI2 and that low expression of miR-506 is associated with poor prognoses in ovarian and breast cancers. This study investigated the role of miR-506 in survival and the EMT in patients with gastric cancer.
METHODS:

In this study, miR-506 and SNAI2 mRNA levels were measured in 141 cases of gastric cancer by quantitative reverse transcription polymerase chain reaction, and the protein expressions of SNAI2 and E-cadherin in 39 cases were validated by immunohistochemical analysis. Next, the associations between their expression levels and clinicopathologic factors were evaluated. In addition, cell proliferation, migration, and luciferase activity of the 3' untranslated region (UTR) of SNAI2 were analyzed using pre-miR-506 precursor in two human gastric cancer cell lines.
RESULTS:

Low expression of miR-506 was significantly correlated with poor overall survival in both the univariate analysis (P = 0.016) and the multivariate analysis (P < 0.05). Low miR-506 expression was significantly correlated with high SNAI2 expression (P = 0.009) and poorly differentiated type (P = 0.015). In vitro, miR-506 suppressed SNAI2 expression by binding to its 3'UTR, resulting in increased expression of E-cadherin (P < 0.05), verified by immunohistochemical analysis. Pre-miR-506 transfected cells showed significantly suppressed cell proliferation and migration (P < 0.05) compared with the control cells.
CONCLUSIONS:

The EMT was directly suppressed by miR-506, and its low expression was an independent prognostic factor in gastric cancer patients. The data indicated that miR-506 may act as a tumor suppressor and could be a novel therapeutic agent.

DOI： 10.1245/s10434-015-4418-2

Language：English   Publishing type：Research paper (scientific journal)  

The gene encoding F-box protein FBXW7 is frequently mutated in many human cancers. Although most previous studies have focused on the tumor-suppressive capacity of FBXW7 in tumor cells themselves, we determined that FBXW7 in the host microenvironment also suppresses cancer metastasis. Deletion of Fbxw7 in murine BM-derived stromal cells induced accumulation of NOTCH and consequent transcriptional activation of Ccl2. FBXW7-deficient mice exhibited increased serum levels of the chemokine CCL2, which resulted in the recruitment of both monocytic myeloid-derived suppressor cells and macrophages, thereby promoting metastatic tumor growth. Administration of a CCL2 receptor antagonist blocked the enhancement of metastasis in FBXW7-deficient mice. Furthermore, in human breast cancer patients, FBXW7 expression in peripheral blood was associated with serum CCL2 concentration and disease prognosis. Together, these results suggest that FBXW7 antagonizes cancer development in not only a cell-autonomous manner, but also a non-cell-autonomous manner, and that modulation of the FBXW7/NOTCH/CCL2 axis may provide a potential approach to suppression of cancer metastasis.

DOI： 10.1172/JCI78782

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND:

RNA polymerase 1 transcription termination factor (TTF1) mediates the transcription of ribosomal RNA (rRNA). In the current study, we investigated the clinical and biological significance of the TTF1 gene in colorectal cancer (CRC).
METHODS:

The expression of TTF1 messenger RNA (mRNA) in tumor and normal tissues from 136 patients with CRC was examined by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). We also performed in vitro cell proliferation and migration assays in TTF1-expressing CRC cells. The biological role of TTF1 in CRC was further elucidated using gene set enrichment analysis (GSEA) with CRC samples.
RESULTS:

TTF1 expression was significantly higher in tumor tissues than in corresponding normal tissues (p = 0.016). In clinicopathological analysis, the high-TTF1 expression group showed a higher incidence of liver metastasis and lymphatic invasion than the low-TTF1 expression group (p < 0.05), and tended to have more frequent venous invasion than the low-TTF1 expression group. Furthermore, the high-TTF1 expression group had a significantly poorer prognosis than the low-TTF1 expression group (p = 0.011). Moreover, overexpression of TTF1 enhanced the proliferation and migration capacity of CRC cells in vitro. GSEA revealed that TTF1 was significantly associated with the RAS and MYC pathways, and this observation was confirmed in samples from 136 patients with CRC.
CONCLUSION:

TTF1 was involved in cancer progression via the RAS and MYC pathways in CRC, suggesting that TTF1 may be a prognostic indicator and therapeutic target in CRC.

DOI： 10.1245/s10434-015-4652-7

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND/AIM:

MiR-15a targets Cyclin E1 (CCNE1), which regulates the cell cycle and promotes cell proliferation and progression. Herein, we investigated the clinicopathological significance of miR-15a as a prognostic marker in breast cancer (BC) cases.
MATERIALS AND METHODS:

We collected primary tumor samples of 230 BC cases, including 68 triple-negative cases. The expression levels of miR-15a in primary tumors were measured by qRT-PCR assay.
RESULTS:

Low expression of miR-15a in primary tumors was significantly correlated with shorter disease-free survival (p=0.0012) and overall survival (p=0.005) compared to the high miR-15a expression in triple-negative BC cases. Multivariate analysis indicated that low miR-15a expression was an independent prognostic factor for overall survival [RR=2.56(1.03-7.18), p=0.04].
CONCLUSION:

MiR-15a expression levels could be a promising biological and prognostic marker for overall survival especially in triple-negative BC cases.

Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.
KEYWORDS:

breast cancer; miR-15a; prognosis

Language：English   Publishing type：Research paper (scientific journal)  

Cancer-associated fibroblasts (CAFs) have recently been linked to the invasion and metastasis of gastric cancer. In addition, the microRNA (miR)-200 family plays a central role in the regulation of the epithelial-mesenchymal transition process during cancer metastasis, and aberrant DNA methylation is one of the key mechanisms underlying regulation of the miR-200 family. In this study, we clarified whether epigenetic changes of miR-200b by CAFs stimulate cancer invasion and peritoneal dissemination in gastric cancer. We evaluated the relationship between miR-200b and CAFs using a coculture model. In addition, we established a peritoneal metastasis mouse model and investigated the expression and methylation status of miR-200b. We also investigated the expression and methylation status of miR-200b and CAFs expression in primary gastric cancer samples. CAFs (CAF-37 and CAF-50) contributed to epigenetic changes of miR-200b, reduced miR-200b expression and promoted tumor invasion and migration in NUGC3 and OCUM-2M cells in coculture. In the model mice, epigenetic changes of miR-200b were observed in the inoculated high-frequency peritoneal dissemination cells. In the 173 gastric cancer samples, the low miR-200b expression group demonstrated a significantly poorer prognosis compared with the high miR-200b expression group and was associated with peritoneal metastasis. In addition, downregulation of miR-200b in cancer cells was significantly correlated with alpha-smooth muscle actin expression. Our data provide evidence that CAFs reduce miR-200b expression and promote tumor invasion through epigenetic changes of miR-200b in gastric cancer. Thus, CAFs might be a therapeutic target for inhibition of gastric cancer.

DOI： 10.1093/carcin/bgu232

Language：English   Publishing type：Research paper (scientific journal)  

Cancer-associated fibroblasts (CAFs) have recently been linked to the invasion and metastasis of gastric cancer. In addition, the microRNA (miR)-200 family plays a central role in the regulation of the epithelial-mesenchymal transition process during cancer metastasis, and aberrant DNA methylation is one of the key mechanisms underlying regulation of the miR-200 family. In this study, we clarified whether epigenetic changes of miR-200b by CAFs stimulate cancer invasion and peritoneal dissemination in gastric cancer. We evaluated the relationship between miR-200b and CAFs using a coculture model. In addition, we established a peritoneal metastasis mouse model and investigated the expression and methylation status of miR-200b. We also investigated the expression and methylation status of miR-200b and CAFs expression in primary gastric cancer samples. CAFs (CAF-37 and CAF-50) contributed to epigenetic changes of miR-200b, reduced miR-200b expression and promoted tumor invasion and migration in NUGC3 and OCUM-2M cells in coculture. In the model mice, epigenetic changes of miR-200b were observed in the inoculated high-frequency peritoneal dissemination cells. In the 173 gastric cancer samples, the low miR-200b expression group demonstrated a significantly poorer prognosis compared with the high miR-200b expression group and was associated with peritoneal metastasis. In addition, downregulation of miR-200b in cancer cells was significantly correlated with alpha-smooth muscle actin expression. Our data provide evidence that CAFs reduce miR-200b expression and promote tumor invasion through epigenetic changes of miR-200b in gastric cancer. Thus, CAFs might be a therapeutic target for inhibition of gastric cancer.

DOI： 10.1093/carcin/bgu232

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND:

Human CDCP1 gene, located on chromosome 3p21.3, is a transmembrane glycoprotein widely expressed in epithelial tissues, and its role in cancer remains to be understood.
METHODS:

Using microarray profiles of gene expression and copy number data from 69 esophageal squamous cell carcinoma (ESCC) samples, we performed informatics analyses to reveal the significance of CDCP1 expression. We also performed migration and invasion assays of siRNA-targeted CDCP1-transfected cells and CDCP1-overexpressing cell in vitro. Moreover, we evaluated the clinical magnitude of CDCP1 expression in esophageal squamous cell cancer cases.
RESULTS:

Allelic loss of chromosome 3p was confirmed by copy number analysis. The expression level of CDCP1 in tumor tissue was significantly lower than that in corresponding normal tissue. siRNA targeting of CDCP1 promoted the migratory and invasive abilities of esophageal cancer cell lines, whereas both abilities were reduced in CDCP1-overexpressing cells. Gene set enrichment analysis showed that expression levels of CDCP1 were associated with tumor differentiation and metastasis, consistent with the result of clinicopathologic analyses. Finally, multivariate analysis revealed that the expression level of CDCP1 was an independent prognostic factor for survival.
CONCLUSIONS:

Loss of CDCP1 expression may be a novel indicator for biological aggressiveness in ESCC.

DOI： 10.1245/s10434-014-3740-4

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1245/s10434-014-3889-x

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND:

Downregulation of paired related homeobox 1 (PRRX1) is associated with the acquisition of cancer stem cell (CSC)-like properties and poor prognosis in cancers. The purpose of this study is to clarify the role of PRRX1 expression in predicting prognosis and mediating CSC-like properties in hepatocellular carcinoma (HCC).
METHODS:

The association between PRRX1 expression and overall survival (OS) of patients with HCC was analyzed in three independent datasets: 62 resected primary cases, 242 cases from GSE14520, and 162 cases from The Cancer Genome Atlas (TCGA). A cell line expressing PRRX1 (HuH7) was established for the functional analyses. The ability to form spheres, the expression levels of the hepatic CSC surface markers (CD13, CD133, and EpCAM), in vitro chemosensitivity to 5-fluorouracil (FU), and radiosensitivity were evaluated.
RESULTS:

Univariate and multivariate analyses showed that the 5-year OS of the low PRRX1 expression group was significantly poorer than that of the high PRRX1 expression group (P = 0.024 and P = 0.045, respectively). Consistent with this, the low PRRX1 expression group in GSE14520 and TCGA datasets showed significantly shorter OS (P = 0.027 and P = 0.010, respectively). Gene set enrichment analysis on GSE14520 and TCGA datasets indicated that downregulation of PRRX1 was correlated with the stemness signature. The number of spheres and the expression levels of CSC markers were significantly decreased when PRRX1 was expressed. Moreover, PRRX1 impaired resistance to 5-FU and radiation.
CONCLUSIONS:

Downregulation of PRRX1 expression contributes to the poor prognosis of patients with HCC through acquisition of CSC-like properties.

DOI： 10.1245/s10434-014-4242-0

Language：English   Publishing type：Research paper (scientific journal)  

Pyruvate kinase M2 (PKM2) is an alternatively spliced variant of the pyruvate kinase gene that is preferentially expressed during embryonic development and in cancer cells. PKM2 alters the final rate-limiting step of glycolysis, resulting in the cancer-specific Warburg effect (also referred to as aerobic glycolysis). Although previous reports suggest that PKM2 functions in nonmetabolic transcriptional regulation, its significance in cancer biology remains elusive. Here we report that stimulation of epithelial-mesenchymal transition (EMT) results in the nuclear translocation of PKM2 in colon cancer cells, which is pivotal in promoting EMT. Immunoprecipitation and LC-electrospray ionized TOF MS analyses revealed that EMT stimulation causes direct interaction of PKM2 in the nucleus with TGF-β-induced factor homeobox 2 (TGIF2), a transcriptional cofactor repressor of TGF-β signaling. The binding of PKM2 with TGIF2 recruits histone deacetylase 3 to the E-cadherin promoter sequence, with subsequent deacetylation of histone H3 and suppression of E-cadherin transcription. This previously unidentified finding of the molecular interaction of PKM2 in the nucleus sheds light on the significance of PKM2 expression in cancer cells.

DOI： 10.1073/pnas.1407717111

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Depressed and flat surface lesions are not easy to identify with routine colonoscopies during screening for colorectal cancer (CRC). Identifying clinically relevant genes that influence tumor shape could be useful when screening for the presence of depressed lesions. Total RNA was extracted from tumor cells collected by laser microdissection from the primary lesions of 146 CRC cases. Microarray analysis was performed to identify genes that were differentially expressed between depressed and elevated tumors. Single nucleotide polymorphism (SNP) analysis of genomic DNA from the peripheral blood of 67 CRC patients was then used to associate polymorphisms with the occurrence of depressed tumors. Microarray analysis revealed significantly higher expression of the fibronectin 1 (FN1) gene in 129 depressed-type tumors and lesions compared to 17 elevated-type tumors. FN1-abundant CRC tumors were large with a significantly higher incidence of lymphatic permeation. SNP analysis indicated that 44 tumors with a GG genotype at SNP rs6707530 showed significantly higher FN1 expression than did 23 tumors with GT/TT genotypes (p<0.05). The product of the FN1 gene (located at 2q34) is involved in cell adhesion, migration and metastasis in mesenchymal tumors. Abundant expression of FN1 may allow cancer cells to invade deeper layers, which would eventually define tumor shape. Identification of this SNP in blood samples may facilitate disease diagnosis and allow prediction of the presence of depressed tumors in the colorectal epithelium before a colon fiberscope examination.

DOI： 10.3892/or.2014.3251

Language：English  

Language：English  

DOI： 10.1245/s10434-013-3264-3

Language：English   Publishing type：Research paper (scientific journal)  

We previously conducted gene expression microarray analyses to identify novel indicators for colorectal cancer (CRC) metastasis and prognosis from which we identified PVT-1 as a candidate gene. PVT-1, which encodes a long noncoding RNA, mapped to chromosome 8q24 whose copy-number amplification is one of the most frequent events in a wide variety of malignant diseases. However, PVT-1 molecular mechanism of action remains unclear.
METHODS:
We conducted cell proliferation and invasion assays using colorectal cancer cell lines transfected with PVT-1siRNA or negative control siRNA. Gene expression microarray analyses on these cell lines were also carried out to investigate the molecular function of PVT-1. Further, we investigated the impact of PVT-1 expression on the prognosis of 164 colorectal cancer patients by qRT-PCR.
RESULTS:
CRC cells transfected with PVT-1 siRNA exhibited significant loss of their proliferation and invasion capabilities. In these cells, the TGF-β signalling pathway and apoptotic signals were significantly activated. In addition, univariate and multivariate analysis revealed that PVT-1 expression level was an independent risk factor for overall survival of colorectal cancer patients.
CONCLUSION:
PVT-1, which maps to 8q24, generates antiapoptotic activity in CRC, and abnormal expression of PVT-1 was a prognostic indicator for CRC patients.

Language：English  

DOI： 10.1158/1078-0432.CCR-12-3186

Language：English  

DOI： 10.1371/journal.pone.0083629

Language：English  

DOI： 10.1038/bjc.2013.561

Language：English  

DOI： 10.1038/cr.2013.87

Language：English  

DOI： 10.1101/gr.152942.112

Language：English  

DOI： 10.1093/carcin/bgs288

Language：English  

DOI： 10.1245/s10434-012-2246-1

Language：English  

DOI： 10.1245/s10434-012-2278-6

Language：English  

DOI： 10.3892/ijo.2012.1436

Language：English   Publishing type：Research paper (scientific journal)  

Cancer stroma plays an important role in the progression of cancer. Although alterations in miRNA expression have been explored in various kinds of cancers, the expression of miRNAs in cancer stroma has not been explored in detail.
EXPERIMENTAL DESIGN:
Using a laser microdissection technique, we collected RNA samples specific for epithelium or stroma from 13 colorectal cancer tissues and four normal tissues, and miRNA microarray and gene expression microarray were carried out. The expression status of miRNAs was confirmed by reverse transcriptase PCR. Furthermore, we investigated whether miRNA expression status in stromal tissue could influence the clinicopathologic factors.
RESULTS:
Oncogenic miRNAs, including two miRNA clusters, miR-17-92a and miR-106b-25 cluster, were upregulated in cancer stromal tissues compared with normal stroma. Gene expression profiles from cDNA microarray analyses of the same stromal tissue samples revealed that putative targets of these miRNA clusters, predicted by Target Scan, such as TGFBR2, SMAD2, and BMP family genes, were significantly downregulated in cancer stromal tissue. Downregulated putative targets were also found to be involved in cytokine interaction and cellular adhesion. Importantly, expression of miR-25 and miR-92a in stromal tissues was associated with a variety of clinicopathologic factors.
CONCLUSIONS:
Oncogenic miRNAs were highly expressed in cancer stroma. Although further validation is required, the finding that stromal miRNA expression levels were associated with clinicopathologic factors suggests the possibility that miRNAs in cancer stroma are crucially involved in cancer progression. Clin Cancer Res; 18(11); 3054-70. ©2012 AACR.

Language：English   Publishing type：Research paper (scientific journal)  

The functional impact of recently discovered long noncoding RNAs (ncRNAs) in human cancer remains to be clarified. One long ncRNA which has attracted attention is the Hox transcript antisense intergenic RNA termed HOTAIR, a long ncRNA expressed from the developmental HOXC locus located on chromosome 12q13.13. In cooperation with Polycomb complex PRC2, the HOTAIR long ncRNA is reported to reprogram chromatin organization and promote breast cancer metastasis. In this study, we examined the status and function of HOTAIR in patients with stage IV colorectal cancer (CRC) who have liver metastases and a poor prognosis. HOTAIR expression levels were higher in cancerous tissues than in corresponding noncancerous tissues and high HOTAIR expression correlated tightly with the presence of liver metastasis. Moreover, patients with high HOTAIR expression had a relatively poorer prognosis. In a subset of 32 CRC specimens, gene set enrichment analysis using cDNA array data revealed a close correlation between expression of HOTAIR and members of the PRC2 complex (SUZ12, EZH2, and H3K27me3). Our findings suggest that HOTAIR expression is associated with a genome-wide reprogramming of PRC2 function not only in breast cancer but also in CRC, where upregulation of this long ncRNA may be a critical element in metastatic progression.

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

DOI： 10.1158/1078-0432.CCR-04-1894

DOI： 10.1158/0008-5472.CAN-05-2509

DOI： 10.1158/0008-5472.CAN-05-2509

Language：English  

DOI： 10.1158/1078-0432.CCR-04-0849

DOI： 10.1038/sj.onc.1206378

DOI： 10.1038/nm0697-593

Publishing type：Research paper (scientific journal)  

DOI： 10.1136/gut.38.1.66

Country：United States  

INTRODUCTION The fragile histidine triad (FHIT) functions as a tumor suppressor and clinical benefits of adenoviral-FHIT (Ad-FHIT) may be expected. However, the pathways through which FHIT induces apoptosis and inhibits cancer cell growth are not known. To determine appropriate targets for Ad-FHIT mediated therapy, we performed microarray analysis between Ad-FHIT transfected cells and control cells using 3 kinds of squamous cancer cell lines. For this purpose, 1) we identified clusters of more repressed genes in Ad-FHIT cells compared to control cells, and 2) we compared clustered genes in apoptosis induced cells H1299 and TE4 by Ad-FHIT infection with genes in non apoptotic non-induced cell line, TE2.
METHOD Three cell lines, H1299, TE4 and TE2 were transfected individually with full length FHIT and lacZ cDNA as a control. Total RNAs extracted from Ad-FHIT or AdlacZ infected samples were labeled with Cy3-dCTP or Cy5-dCTP and hybridized with a chip printed with 19,200 oligos. 1) The Ad-FHIT/Ad-control expression ratio was derived by using a random permutation test with high reproducibility from 7 repetitive
Experiments, and 4 spots per gene on a chip. 2) The expression ratio of TE4/TE2 for eachgene was calculated to determine what genes are dominant in Ad-FHIT induced apoptotic cells.
RESULTS 1) We identified clusters of genes reduced in Ad-FHIT, such as arachidonicacid metabolism (Table 1A) and matrix metalloprotease (MMP) related genes (Table 1B). We confirmed a reduction of PGE2 synthesis to 0.75 times control cells (range 0.35 to 0.98) by ELISA assays after exposure to LPS, IL-1 beta, or PMA stimulation in FHIT expressing cells. 2) The expression ratio of TE4 (apoptosis induced) /TE2 (non-apoptosis induced), disclosed that c-Src tyrosine kinase, tyrosine-protein kinase JAK-1 and EST (#Hs.268892) were associated with apoptosis, with ratios of 2.1, 2.4 and 6.6, respectively(Table 2).

CONCLUSION 1) We anticipate that Ad-FHIT may be effective in certain pre-malignant cases involving inflammatory carcinogens, such as COX-2 which leads to the inhibition of apoptosis; invasion, cell proliferation, angiogenesis mediated by the PGE2 receptor Ep4; IL-1 beta which stimulates the release of prostaglandin; and ERG-1 which is a transcription factor for mPGES. Moreover, the MMP family could be a target of the Ad-FHIT gene. 2) Therefore we predict the induction of apoptosis by Ad-FHIT on far advanced esophageal cancer cases with activation of those signal pathways.

Presentation type：Symposium, workshop panel (public)  

Venue：San Diego   Country：United States  

MAL expression is diminished in esophageal cancer cases and cell lines.
MAL expression in tumor cells exerts an anti-tumorigenic effect by Fas and/or by keratins of esophageal epithelium.
MAL expression is diminished in pre-cancerous lesions in a rat carcinogenic model, as well as in dysplastic lesions of esophageal cancer.

Event date： 2023.5

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：別府   Country：Japan  

Event date： 2023.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：別府   Country：Japan  

Event date： 2022.12

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：web   Country：Japan  

Event date： 2022.12

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：福島   Country：Japan  

Event date： 2022.11

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：盛岡   Country：Japan  

Event date： 2022.9 - 2023.7

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：横浜   Country：Japan  

Event date： 2022.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：web   Country：Japan  

Event date： 2022.7

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：横浜   Country：Japan  

Event date： 2022.6 - 2022.7

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：金沢   Country：Japan  

Event date： 2022.6

Language：English   Presentation type：Symposium, workshop panel (public)  

Venue：札幌   Country：Japan  

Event date： 2022.2

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：web   Country：Japan  

Event date： 2022.2

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：web   Country：Japan  

Event date： 2021.11

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：仙台   Country：Japan  

Event date： 2020.10

Language：English   Presentation type：Oral presentation (general)  

Venue：web（上海）   Country：China  

Event date： 2020.10

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：大阪   Country：Japan  

Event date： 2020.10

Language：English  

Venue：web   Country：Japan  

Event date： 2020.1

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：東京   Country：Japan  

Event date： 2019.12

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：福岡   Country：Japan  

Event date： 2019.11

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：熊本   Country：Japan  

Event date： 2019.5

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京   Country：Japan  

Event date： 2018.11

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：神奈川   Country：Japan  

Event date： 2018.11

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：東京   Country：Japan  

Event date： 2018.11

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京   Country：Japan  

Event date： 2018.7

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：横浜   Country：Japan  

Event date： 2018.7

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：鹿児島   Country：Japan  

Event date： 2018.5

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：札幌   Country：Japan  

Event date： 2018.2

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：名古屋   Country：Japan  

Event date： 2017.12

Language：Japanese   Presentation type：Oral presentation (invited, special)  

Venue：奈良   Country：Japan  

Event date： 2017.10

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：金沢   Country：Japan  

Event date： 2017.10

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：横浜   Country：Japan  

Event date： 2017.10

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：福岡   Country：Japan  

Event date： 2017.10

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：札幌   Country：Japan  

Event date： 2017.7

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：大阪   Country：Japan  

Event date： 2017.7

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：金沢   Country：Japan  

Event date： 2017.7

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：大阪   Country：Japan  

Event date： 2017.6

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：軽井沢   Country：Japan  

Event date： 2017.6

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京   Country：Japan  

Event date： 2017.3

Language：Japanese   Presentation type：Public lecture, seminar, tutorial, course, or other speech  

Venue：大分   Country：Japan  

Event date： 2017.2

Language：Japanese  

Country：Japan  

Event date： 2017.1

Language：Japanese  

Venue：福岡   Country：Japan  

Event date： 2017.1

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Event date： 2016.11

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：金沢   Country：Japan  

Event date： 2016.11

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：山口   Country：Japan  

Event date： 2016.7

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：神戸   Country：Japan  

Event date： 2016.7

Language：Japanese   Presentation type：Public lecture, seminar, tutorial, course, or other speech  

Venue：神戸   Country：Japan  

Event date： 2016.7

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：米子   Country：Japan  

Event date： 2016.7

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：徳島   Country：Japan  

Event date： 2016.7

Language：English   Presentation type：Symposium, workshop panel (public)  

Venue：徳島   Country：Japan  

Event date： 2015.7

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：大阪   Country：Japan  

Event date： 2013.2

Language：English   Presentation type：Oral presentation (general)  

Venue：ハワイ・マウイ   Country：United States  

Event date： 2012.10

Language：Japanese   Presentation type：Oral presentation (invited, special)  

Venue：神戸   Country：Japan  

Event date： 2012.9

Language：Japanese   Presentation type：Public lecture, seminar, tutorial, course, or other speech  

Venue：札幌   Country：Japan  

Event date： 2012.6

Presentation type：Symposium, workshop panel (public)  

Country：Japan  

SNP analysis : rs6983267 is the oncogenesis associated SNP in Japanese CRC (OR;1.16, p=0.0015)
Expression array: Genes in CRC cells of risk allele were significantly associated with MYC gene set by EEM analysis. aCGH: CRC with risk allele of 8q24 showed global CNA and subsequent to the poor prognosis.

Event date： 2012.4

Venue：ホテルニューオータニ幕張   Country：Japan  

わが国における消化器癌患者数および死亡率は増加傾向にある。癌死を改善する最善の策は早期診断・早期治療であるが、個別に発癌リスクが正確に予測できれば、リスクに応じた検査や治療を行うことが可能になる。われわれは特に罹患率が最も高い大腸癌と悪性度が最も高い食道癌を対象に、遺伝学的因子（遺伝子多型）と環境疫学因子とについて、それぞれの発癌リスクを明らかにした。

１）大腸癌：全国９機関の研究協力体制のもと全3609例(症例群1511例、対照群2098例)を集積し、大腸発癌に関するゲノムワイド関連研究(GWAS)および144項目に及ぶアンケート解析を実施した。10p14に４つの多型を同定し危険率1.27 (1.16-1.39) (p=9.31E-08)であった。また疫学因子では高頻度肉食、20歳時BMI、糖尿病が危険因子でありツナ食、ビタミン剤内服が防御因子であった。10p14危険多型と糖尿病との有意な交互作用(2倍, p<0.01)を認めた。

２）食道癌：全例2200例(症例群1100例、対照群1100例)を集積し食道発癌関連GWAS解析および生活習慣アンケートを実施した。多型解析の結果、アルコール代謝に重要な役割を果たすADH1B, ALDH2遺伝子多型がそれぞれオッズ比4.08 (P 値4.4E-40) 、オッズ比4.13 (P値10E-76) と食道癌患者と健常者の間に著しい差を示した。これらが飲酒と関係する遺伝子であること、また喫煙が食道癌発症に関与するために、これらの遺伝子多型と飲酒・喫煙との交互作用を検討した。その結果、これら4つの因子を全て有する場合、全く有しないヒトと比較して、食道癌発症の危険率は146倍高いことを示した。

　食道癌患者には生活習慣および遺伝子多型が危険因子は非危険因子に比べて100倍以上高いリスクを示す集団が存在し、大腸癌に関してはリスクの合計により3.6倍以上のリスクを有する集団が存在した。ハイリスク群として今後頻回の検診が必要であることを明らかにした。

Event date： 2012.3

Language：English   Presentation type：Oral presentation (general)  

Venue：オーランド   Country：United States  

Event date： 2011.7 - 2012.7

Presentation type：Symposium, workshop panel (public)  

Venue：名古屋国際会議場   Country：Japan  

【目的】8q24多型genotypeと実際の臨床検体におけるMYC発現との関連を明らかにした報告はない。本多型がMYCを介してDNA複製を促進して発癌に寄与するのであれば、大腸癌進展・予後にも寄与することが推察される。本研究では、8q24多型のgenotypeの臨床的意義を明らかにするとともに大腸癌ゲノムコピー数変異との関係をDukes病期別に調べ、大腸癌進展との関連を明らかにする。さらに多型と関連する機能性遺伝子群を(発現モジュール抽出)EEM解析法で明らかにする。
【対象と方法】１）大腸癌157症例原発巣よりgenomic DNAとtotal RNAを抽出し、それそれCGHアレイと発現アレイを実施した。２）遺伝子多型情報を有する102例については最も重要な遺伝子多型locus 8q24について、その発癌機構を解明するため、そのgenotypeとCGHアレイ、あるいは発現アレイprofileとをした。また、既知のMSI,p53,K-ras,B-rafのstatusについても解析を行った。
【結果】1)大腸癌原発巣における大腸癌細胞におけるMYC発現は8q24多型のgenotypeと有意に相関しており、Tuupananenらの報告を実際の臨床癌細胞において再現した。2)大腸癌原発巣において、rs6983267(8q24)多型はrisk alleleを有する大腸癌症例は、Dukes分類においても高度進展症例群において有意に多かった。3)上述した多型と大腸癌進展との関連が、MYCに起因する結果であることを確認するために、大腸癌ゲノムコピー数変異と多型との関係をDukes分類別に解析した。その結果、リスクアリルを有する症例群のゲノムコピー数変化（増減の絶対値）は、非リスクアリルを有する症例群にくらべて、大腸癌進展に伴い（Dukes ABからCDになるに伴い）、その変化が有意に大きいことを明らかにした。4)EEM解析の結果、細胞機能関連遺伝子群(IPAFUNCモジュール)では8q24多型とDNA複製関連遺伝子群とが相関することを明らかにし、癌関連遺伝子群(NevinsSigUDモジュール)ではMYC関連遺伝子群が極めて有意に相関していることを明らかにした。
【結論と考察】8q24多型と相関するMYC発現がその関連分子群すべての遺伝子群の発現と相関していることをEEM解析にて明らかにした。すなわち、多型と相関するMYCを介したDNA複製が大腸癌進展に関与することをスーパーコンピュータ解析で証明された。大腸癌のゲノムのクラスター分類は、ゲノム変異の乏しいグループ１(MIN)とダイナミックな変異を示すグループ２(CIN)に分かれた。CINをきたす要因として8q24多型にともなうMYC発現増加が関連する傾向を示したが有意差はない。大腸癌は遺伝子的要因に加え環境要因も複雑に絡む多因子疾患であり、ひとつずつ丁寧に解明することにより生命予後の改善に寄与したい。

Event date： 2011.6

Presentation type：Symposium, workshop panel (public)  

Country：Japan  

１）大腸癌：全国９機関の研究協力体制を確立し、アンケート、血液サンプル(全3609例:症例群1511例、対照群2098例)を集積。解析を実施した。全ゲノム相関解析による大腸癌発症関連遺伝子多型の探索を行いスクリーニング(GWAS)を実施した結果10p14に４つの多型を同定した。このうち最も有意であったgenotypeはアリル頻度差6%、オッズ比1.27(1.16-1.39)、p値は9.31E-08であった。また大腸がんの症例対照研究の結果、高頻度肉食、20歳時BMI、糖尿病が危険因子。ツナ食、ビタミン剤内服が防御因子であった。10p14危険多型と糖尿病との有意な交互作用(2倍, p<0.01)を明らかにした。一方、既知の多型8q24についても、上記邦人症例においてオッズ比1.16倍(1.06-1.27)、p値0.0015と有意な大腸発癌関連多型であることを証明し、同多型は予後因子となりうることを証明した。また8q24非危険多型集団は糖尿病により有意に発癌リスクが高まることを示した。

２）食道癌：食道癌の生活習慣アンケートおよび多型解析用の血液を(全例2200例：症例群1100例、対照群1100例)を集積した。多型解析の結果、アルコール代謝に重要な役割を果たすADH1B, ALDH2遺伝子多型がそれぞれオッズ比4.08, P 値4.4E-40 、オッズ比4.13, P値10E-76 と食道癌患者と健常者の間に著しい差を示した。これらが飲酒と関係する遺伝子であること、また喫煙が食道癌発症に関与するために、これらの遺伝子多型と飲酒・喫煙との交互作用を検討した。その結果、これら4つの因子を全て有する場合、全く有しないヒトと比較して、食道癌発症の危険率は146倍高いことを示した。

　以上の様に食道癌では生活習慣および遺伝子多型が危険因子は非危険因子に比べて100倍以上大きな示した一方で、大腸癌は多型あるいは疫学因子における危険因子がそれぞれ2倍未満であり、大腸発癌が多因子疾患であることを改めて大規模症例研究で明らかにした。

Event date： 2010.7

Presentation type：Oral presentation (general)  

Country：Greece  

Event date： 2010.7

Presentation type：Symposium, workshop panel (public)  

Country：Japan  

Event date： 2010.7

Presentation type：Symposium, workshop panel (public)  

Country：Japan  

Venue：Washington DC   Country：United States  

Introduction: This report examines the clinical outcomes of cancer patients after 12 post-operative years to determine the prognostic value of CEA mRNA in peripheral blood (PB) (Mori M., JCO 1997). In addition, a novel ITC marker, identified by microarray analysis, was validated with 959 cases of gastric cancer (GC) by Taqman RT-PCR.
Patients and methods: 1) The clinical outcomes of 102 cases were reinvestigated and compared to evaluate CEA expression in PB. 2) Metastatic-related genes present in bone marrow (BM) were identified by cDNA microarray analysis of total RNA from the whole blood of four metastatic and four non-metastatic cases. Among the up-regulated genes in the metastatic cases, MT1MMP was chosen for further analysis. 3) MT1MMP expression was validated by Taqman RT-PCR using the PB and BM from 959 cases of GC.
Results: 1) Among 102 cases, 12 that were CEA (-) showed novel distant metastasis; however, the incidence of CEA in PB was not associated with OS and DFS. 2) Expression levels of MT1MMP were up-regulated in metastases. MT1MMP1 localizes to the cell surface to regulate tumor invasion, and is expressed from cancer cells and/or interstitial cells via cell-cell interactions. 3) The positive rate of GC cases with MT1MMP expression in PB was larger in 13 (72%) cases with distant metastasis than in 296 (31%) cases without distant metastasis (p=0.0002). Five (27.8%) cases with distant metastasis showed a higher incidence of MT1MMP (+) in BM compared with 71 (7.3%) cases without distant metastasis. Furthermore, 3 (25%) cases with recurrence were MT1MMP (+) in BM, while 73 (7.5%) cases without recurrence were MT1MMP (-) in BM, a significant association (p=0.020).
Conclusion: Based on the long follow-up period, we conclude that presence of the epithelial marker CEA in PB cannot be used as a prognostic or recurrent marker for GC. This large-scale study revealed that MT1MMP expression could be an effective predictor of clinical outcome in GC cases. In GC, metastasis from primary cancer tissues may require cancer cells with high metastatic potential and/or circumstances, such as MT1MMP expression in PB or BM.

Venue：Chicago   Country：United States  

Introduction To predict the cancer recurrence, the evaluation of isolated tumor cells (ITC) in the peripheral blood (PB) or bone marrow (BM) by using epithelial cell markers such as CEA or cytokeratins (CK) would be useful. On the other hand, the significance of the expression of cancer related genes such as urokinase type plasminogen activator receptor (u-PAR) in PB or BM has not been clarified.
Patients and Methods 1) We examined ITC in PB and BM from 744 cases of breast cancer (and 29 non-malignant patients as a negative control) by the quantitative real-time RT-PCR with CEA, CK-19, and CK-7. The ITC positive was determined when each one of the three genes was expressed. 2) The expressions of u-PAR in PB and BM were examined by real time RT-PCR. 3) We combined data of u-PAR and CK in comparison with each gene. 4) Serum CEA and CA15-3 levels in 298 of 744 cases were measured to compare with the u-PAR or CK status.
Results 1) The positive result was recognized in 262 (35.4%) cases in PB, and these showed poorer disease free survival than 482 negative cases (p<0.05). 2) The 169 cases of u-PAR (+) BM showed significantly poorer disease free survival and overall survival than 575 cases of u-PAR (-) BM (p<0001 and p <0.0001, respectively). In PB, a significant difference was also observed between 309 cases of u-PAR (+) and 435 cases of u-PAR (-) (p<0.0001). 3) As for the combination of u-PAR and CK in BM, u-PAR (+)/CK(+) showed the highest recurrence rate, however, u-PAR status alone was adequate to predict recurrence in comparison with the combined data. 4) The hazard ratio for prediction of recurrence are significantly higher in u-PAR (p<0.0001; HR 0.0519) than serum CEA or CA15-3 level (not significant).
Conclusion We found that the significance of u-PAR was much greater than the ITC alone. This means that the tumor-host reactions (one of those parameters may be the u-PAR) would be very important to predict the cancer recurrence rather than the existence of cancer cells in the circulating system, and would be much more reliable than the established serum tumor markers preoperatively.

Language：Japanese   Presentation type：Public lecture, seminar, tutorial, course, or other speech  

Country：Japan  

食道進行癌は治療抵抗性で予後不良である。治療成績向上のためには食道癌の発生、進展に関わる因子を総合的かつ俯瞰的に明らかにすることが重要である。
１）GWASと疫学因子解析：われわれは食道癌1071名の患者と2762名の対照者について遺伝子多型および環境要因を同時に解析することにより食道発癌危険因子を明らかにした。(1)GWASの結果：ADH1B (4q23)およびALDH2 (12q24.12)というアルコール・アルデヒド代謝経路の遺伝子多型が食道癌の易罹患性に深く関わることが示された。（2）飲酒と喫煙は食道癌発症関与し、交互作用を有する;飲酒・喫煙・ADH1B・ALDH2全てにおいて危険がある場合、一つも無い場合に比べて357倍食道癌に罹患しやすいことを明らかにした。
２）エキソーム解析：　われわれは上記食道癌症例のうち代表的散発性食道癌59例の原発巣および健常組織よりLMDを用いて目的細胞のgenomic DNAおよびRNAを採取後、次世代シークエンサー NGS (Hiseq 2000 platforms)および発現アレイを用いた解析を実施した。depthの平均は94,4、10,837個のnon-synonymous変異をcodingまたはsplice siteに認めた。このうち7004個がmissense変異、226個がshort insertion/deletionであった。TP53を筆頭に、頭頸部癌で既知のNOTCH1遺伝子などに高頻度に変異を認めた。また、変異のスペクトラムを調べたところ３つのパターンにクラスタリングされ、特に遺伝子多型から推察されるアルコール代謝能のレベルと３つのクラスターとの間に関連が認められた。食道癌において飲酒とゲノム変異との関連を示す最初の解析結果となった。

Language：Japanese   Presentation type：Oral presentation (invited, special)  

Country：Japan  

掌蹠の過角化を主症状とする遺伝性掌蹠角化症の中で高率に食道扁平上皮癌を発症するTylosisという亜型が報告されている。Tylosisは常染色体優性遺伝を示すが、この家系では65歳までに罹患者の95%が食道扁平上皮癌を発症する。連鎖解析では本疾患の原因遺伝子が17q25.1上に存在することが示唆されTylosis Oesophageal Cancer (TOC) locusと命名されている。
　われわれは、散発性食道癌においてTOC領域に高頻度のLOHが認められることから、食道扁平上皮癌の原因遺伝子がこの領域に存在する可能性を報告した（Gastroenterology Iwaya et al., 1998.）。1990年代後半から近年までの間にさらに詳細な連鎖解析がなされ、TOC locusは1cM（モルガン）から50-500 kbの領域に狭められた。この領域内に存在する多くの遺伝子の解析がTylosisあるいは散発性食道癌患者を対象に行われてきた(Hum Mol Genet Kelsell DP et al.,1996, Hum Genet McRonald FE, 2006)。Tylosis家系からの解析ではCYGB遺伝子のメチル化(Hum Genet McRonald FE, 2006)やごく最近ではRHBDF2遺伝子の変異が報告されている(Am J Hum Genet, Blaydon DC et al., 2012)。散発性食道癌における解析ではEVPL遺伝子の低頻度の変異（5%）が見られたが (Oncol Rep, Iwaya et al.,2005)、他に食道扁平上皮癌に特異的な変異は同定できていなかった。現段階ではTylosis/食道扁平上皮癌の原因遺伝子その発癌メカニズムは明らかになっていない。
　上述の歴史的経緯を踏まえた上で、17q25.1上に存在することが期待される散発性食道癌あるいは家族性食道癌においても原因となる遺伝子を明らかにするために研究を行った。
　われわれは散発性食道癌60例について、原発巣および健常組織よりLMDを用いて目的細胞のみ採取した上で、次世代シークエンサーを用いた解析(RNA SeqおよびExome解析)を試み、候補遺伝子についてはin vitro, in vivoで確認した。
　RNA-seq解析では、食道癌組織で正常粘膜に比しEVPLとST6GALNAC1遺伝子の有意な発現低下が見られた。特に、ST6GALNAC1では腫瘍特異的な変異は低頻度であり、さらにメチル化による不活化の可能性が示唆された。さらに、Exome解析で17q25.1 TOC locus上の変異についてのデータを採取し、現在鋭意解析中である。
　日本では本症例の遺伝性掌蹠角化症の様な他の併存疾患なく明確に食道癌のみの家族性発症の報告はない。したがって、本発表では、併発疾患を有する食道癌症例で明らかにされている責任ゲノム領域から調べた食道癌の原因遺伝子同定への軌跡について述べる。

Language：Japanese  

Language：Japanese  

Language：Japanese