記述言語：英語   出版者・発行元：Anticancer Research  

Background/Aim: Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy with poor survival rates. Effective molecular-targeted therapies are urgently needed. This study aimed to identify novel candidate tumor-associated genes in ESCC by analyzing chromosomal amplification regions. Materials and Methods: DNA copy number variation (CNV) and mRNA expression data were obtained from The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia (CCLE). Single-cell RNA sequencing data from Gene Expression Omnibus (GEO) were analyzed using Scanpy. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded (FFPE) ESCC tissues. PDCD10 was identified as a potential tumor-associated gene, and its association with clinicopathological factors and prognostic impact was evaluated using Kaplan-Meier survival and Cox regression analyses. Pathway analysis was performed to investigate the biological processes, and drug sensitivity profiling was conducted to identify compounds whose efficacy correlated with PDCD10 expression in ESCC cell lines. Results: PDCD10, a signaling protein involved in cell proliferation and vascular development, showed significant amplification and over-expression in ESCC cases. High PDCD10 expression was associated with poor prognosis. Single-cell RNA sequencing confirmed its tumor-specific expression. GSEA revealed enrichment of mTORC1 signaling, E2F, and Myc target pathways in high PDCD10-expressing tumors. Drug sensitivity analysis identified Azelaic acid and Rebamipide as compounds whose efficacy correlated with PDCD10 expression in ESCC cell lines. Conclusion: PDCD10 could be a novel tumor-associated gene associated with tumor progression and poor prognosis in ESCC. Azelaic acid and Rebamipide are candidate therapeutic agents targeting PDCD10.

DOI： 10.21873/anticanres.17527

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記述言語：英語  

DOI： 10.1007/s13691-025-00748-z

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記述言語：英語   出版者・発行元：Anticancer Research  

Background/Aim: MicroRNAs (miRNAs) have been highlighted as non-invasive clinical biomarkers in liquid biopsy. This study aimed to investigate the clinical significance of circulating tumor suppressors, precursor-miR-488 (pre-miR-488) and miR-488-5p, in the blood of patients with gastric cancer (GC). Materials and Methods: The expression levels of pre-miR-488 and miR-488-5p in tumor tissues and blood were measured using RT-qPCR, and the clinicopathological and prognostic significance of their expression was assessed in patients with GC. Next, pathway analysis of miR-488-5p expression in GC tissues was performed by gene set enrichment analysis (GSEA) using the TCGA dataset. Finally, pre-miR-488 in exosomes from the plasma of GC patients was analyzed using RT-qPCR. Results: Both pre-miR-488 and miR-488-5p were down-regulated in tumor tissues, whereas their expression in the blood was significantly higher in patients with GC than in healthy controls. Low expression of pre-miR-488 or miR-488-5p in the blood was associated with poor prognosis in patients with GC. Furthermore, low pre-miR-488 expression in the blood was an independent poor prognostic factor for overall survival. miR-488-5p expression tended to be negatively correlated with the expression of gene sets involved in epithelial-mesenchymal transition and hypoxia. pre-miR-488 was detected in exosomes isolated from the plasma of patients with GC. Conclusion: Circulating pre-miR-488 and miR-488-5p expression in the blood may serve as novel prognostic biomarkers for patients with GC, predicting clinical outcomes and guiding therapeutic strategies.

DOI： 10.21873/anticanres.17399

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出版者・発行元：Proceedings of the National Academy of Sciences of the United States of America  

Elevated levels of miR-155 in solid and liquid malignancies correlate with aggressiveness of the disease. In this manuscript, we show that miR-155 targets transcripts encoding IcosL, the ligand for Inducible T-cell costimulator (Icos), thus impairing the ability of T cells to recognize and eliminate malignant cells. We specifically found that overexpression of miR-155 in B cells of Eµ-miR-155 mice causes loss of IcosL expression as they progress toward malignancy. Similarly, in mice where miR-155 expression is controlled by a Cre-Tet-OFF system, miR-155 induction led to malignant infiltrates lacking IcosL expression. Conversely, turning miR-155 OFF led to tumor regression and emergence of infiltrates composed of IcosL-positive B cells and Icos-positive T cells forming immunological synapses. Therefore, we next engineered malignant cells to express IcosL, in order to determine whether IcosL expression would increase tumor infiltration by cytotoxic T cells and reduce tumor progression. Indeed, overexpressing an IcosL-encoding cDNA in MC38 murine colon cancer cells before injection into syngeneic C57BL6 mice reduced tumor size and increased intratumor CD8+ T cell infiltration, that formed synapses with IcosL-expressing MC38 cells. Our results underscore the fact that by targeting IcosL transcripts, miR-155 impairs the infiltration of tumors by cytotoxic T cells, as well as the importance of IcosL on enhancing the immune response against malignant cells. These findings should lead to the development of more effective anticancer treatments based on maintaining, increasing, or restoring IcosL expression by malignant cells, along with impairing miR-155 activity.

DOI： 10.1073/pnas.2408649121

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記述言語：英語   出版者・発行元：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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記述言語：英語   出版者・発行元：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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記述言語：英語   出版者・発行元：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。

記述言語：英語   出版者・発行元：European Journal of Cancer  

Background: The mainstream first-line chemotherapy for advanced/recurrent gastric cancer (ARGC) is combination therapy including platinum-based agents. With the progressive aging of the society, the incidence of gastric cancer in elderly patients is increasing. However, elderly patients cannot tolerate these agents because of renal dysfunction or low quality of life. The KSCC1701 study explored the efficacy and safety of S-1 + ramucirumab in elderly patients with ARGC. Patients and methods: Chemotherapy-naive patients aged ≥70 years with ARGC were eligible. Patients received S-1 (40–60 mg twice daily for 4 weeks in 6-week cycles) and ramucirumab (8 mg/kg every 2 weeks) until disease progression. The primary end-point was the 1-year overall survival (OS) rate. The anticipated lower threshold of 1-year survival was set at 40% in light of previous S-1–based regimens. The secondary end-points included progression-free survival (PFS), OS, the overall response rate (ORR) and safety. Results: Between September 2017 and November 2019, 48 patients (34 men and 14 women) were enrolled in this study. The median patient age was 77.5 years, and all patients had a performance status of 0 (n = 20) or 1 (n = 28). The 1-year OS rate was 65.2%, which met the primary end-point. The median survival time and median PFS were 16.4 and 5.8 months, respectively. The ORR was 41.9%. The most frequent grade 3/4 (≥15%) adverse events were neutropenia, anorexia and anaemia. Conclusion: Considering these findings, S-1 + ramucirumab appears to be an excellent treatment option for elderly patients with ARGC. (250 words). This trial has been registered with the Japan Registry of Clinical Trials Registry under the number jRCTs071180066.

DOI： 10.1016/j.ejca.2022.02.028

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DOI： 10.1200/JCO.2022.40.4_suppl.256

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記述言語：英語   出版者・発行元：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。

記述言語：英語   出版者・発行元：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

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s00595-019-01789-7.

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.21873/anticanres.13084.

開催年月日： 2018年9月

記述言語：日本語  

開催地：大阪   国名：日本国  

開催年月日： 2018年9月

記述言語：日本語  

開催地：大阪   国名：日本国  

開催年月日： 2018年9月

記述言語：日本語  

開催地：大阪   国名：日本国  

開催年月日： 2018年9月

記述言語：日本語  

開催地：大阪   国名：日本国  

開催年月日： 2018年9月

記述言語：日本語  

開催地：大阪   国名：日本国  

開催年月日： 2018年6月

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：大分   国名：日本国  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：英語  

記述言語：日本語  

記述言語：英語  

記述言語：英語