記述言語：英語   出版者・発行元：Cell Communication and Signaling  

Background: We previously identified Il17RB, a member of the IL17 superfamily, as a candidate marker gene for endometrial aging. While IL17RB has been linked to inflammation and malignancies in several organ systems, its function in the endometrium has not been investigated and is thus poorly understood. In the present study, we performed a functional analysis of this receptor with the aim of determining the effects of its age-associated overexpression on the uterine environment. Methods: We analyzed IL17RB-related signaling pathways and downstream gene expression in an immortalized human endometrial glandular epithelial cell line (“hEM”) forced to express the receptor via lentiviral transduction (“IL17RB-hEM”). We also prepared endometrial organoids from human endometrial tissue sourced from hysterectomy patients (“patient-derived EOs”) and exposed them to cytokines that are upregulated by IL17RB expression to investigate changes in organoid-forming capacity and senescence markers. We analyzed RNA-seq data (GEO accession number GSE132886) from our previous study to identify the signaling pathways associated with altered IL17RB expression. We also analyzed the effects of the JNK pathway on organoid-forming capacity. Results: Stimulation with interleukin 17B enhanced the NF-κB pathway in IL17RB-hEM, resulting in significantly elevated expression of the genes encoding the senescence associated secretory phenotype (SASP) factors IL6, IL8, and IL1β. Of these cytokines, IL1β inhibited endometrial organoid growth. Bioinformatics analysis showed that the JNK signaling pathway was associated with age-related variation in IL17RB expression. When IL17RB-positive cells were cultured in the presence of IL17B, their organoid-forming capacity was slightly but non-significantly lower than in unexposed IL17RB-positive cells, but when IL17B was paired with a JNK inhibitor (SP600125), it was restored to control levels. Further, IL1β exposure significantly reduced organoid-forming capacity and increased p21 expression in endometrial organoids relative to non-exposure (control), but when IL1β was paired with SP600125, both indicators were restored to levels comparable to the control condition. Conclusions: We have revealed an association between IL17RB, whose expression increases in the endometrial glandular epithelium with advancing age, and cellular senescence. Using human endometrial organoids as in vitro model, we found that IL1β inhibits cell proliferation and leads to endometrial senescence via the JNK pathway.

DOI： 10.1186/s12964-024-01740-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   出版者・発行元：シュプリンガー・ジャパン(株)  

症例は72歳女性、2妊2産であった。卵巣悪性腫瘍に対して52歳時に開腹子宮全摘術、両側卵管卵巣摘出術、大網切除術、骨盤リンパ節郭清術を施行され、最終診断はステージIaの成人型顆粒膜細胞腫(AGCT)であった。初回手術から19年後、他施設で受けたCTで後腹膜腫瘍が偶然発見された。腫瘍は直径11×10cmで、肝門部、下大静脈、右腎静脈が隆起していた。CTガイド下腫瘍生検によりAGCTの再発が確認された。腫瘍が巨大であり、完全切除を行うと出血多量による術中死亡のリスクがあると考えられた。そこで、パクリタキセル+カルボプラチン(PC)による術前化学療法を行い、再発腫瘍を縮小させた。その後、縮小手術を行った。再発腫瘍の完全切除に成功し、手術時間は12時間54分、出血量は700gであった。切除標本の病理所見からAGCTの再発と診断した。術後1年経過時点で再発は認められなかった。

記述言語：英語  

DOI： 10.1007/s13691-024-00659-5

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記述言語：英語   出版者・発行元：Journal of Biological Chemistry  

BHLHE40 is a basic helix-loop-helix transcription factor that is involved in multiple cell activities including differentiation, cell cycle, and epithelial-to-mesenchymal transition. While there is growing evidence to support the functions of BHLHE40 in energy metabolism, little is known about the mechanism. In this study, we found that BHLHE40 expression was downregulated in cases of endometrial cancer of higher grade and advanced disease. Knockdown of BHLHE40 in endometrial cancer cells resulted in suppressed oxygen consumption and enhanced extracellular acidification. Suppressed pyruvate dehydrogenase (PDH) activity and enhanced lactated dehydrogenase (LDH) activity were observed in the knockdown cells. Knockdown of BHLHE40 also led to dephosphorylation of AMPKα Thr172 and enhanced phosphorylation of pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1) Ser293 and lactate dehydrogenase A (LDHA) Tyr10. These results suggested that BHLHE40 modulates PDH and LDH activity by regulating the phosphorylation status of PDHA1 and LDHA. We found that BHLHE40 enhanced AMPKα phosphorylation by directly suppressing the transcription of an AMPKα-specific phosphatase, PPM1F. Our immunohistochemical study showed that the expression of BHLHE40, PPM1F, and phosphorylated AMPKα correlated with the prognosis of endometrial cancer patients. Because AMPK is a central regulator of energy metabolism in cancer cells, targeting the BHLHE40‒PPM1F‒AMPK axis may represent a strategy to control cancer development.

DOI： 10.1016/j.jbc.2024.105695

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記述言語：英語   出版者・発行元：Wiley  

Indocyanine green (ICG) with near-infrared (NIR) fluorescence imaging is used for lymphatic mapping. However, binding of ICG to blood proteins like serum albumin can shorten its retention time in sentinel lymph nodes (SLNs). Here, we investigated the efficacy and safety of a new fluorescence tracer comprising phytate and liposome (LP)-encapsulated ICG. Coadministration of phytate with LP containing phosphatidic acid promotes chelation mediated by Ca^<2+> in bodily fluids to enhance SLN retention. Uniformly sized LPs (100 nm) encapsulating ICG under conditions that minimized fluorescence self-quenching during storage were produced. We analyzed the behavior of the new tracer (ICG-phytate-LP) and control tracers (ICG and ICG-LP) in the lymphatic flow of mice in terms of lymph node retention time. We also tested lymphatic flow and safety in pigs that have a more human-like lymphatic system. LPs encapsulating stabilized ICG were successfully prepared. Mixing LP with phytate in the presence of Ca^<2+> increased both the particle size and negative surface charge. In mice, ICG-phytate-LP had the best lymph node retention, with a fluorescence intensity ratio that increased over 6 h and then decreased slowly over the next 24 h. In pigs, administration of ICG and ICG-phytate-LP resulted in no death or weight loss. There were no obvious differences between blood test results for the ICG and ICG-phytate-LP groups, and the overall safety was good. ICG-phytate-LP may be a useful new tracer for gynecological cancers that require time for lymph node identification due to a retroperitoneal approach.

CiNii Research

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

センチネルリンパ節(SLN)を同定するためのトレーサーとして、リポソーム封入インドシアニングリーン(ICG)とフィチン酸塩で構成される新規な蛍光トレーサーを開発し、その有効性と安全性を調査した。まず、安定化したICGが封入されているリポソームを調製した。次にキレート反応が発揮されることを期待し、Ca2+の存在下でリポソームとフィチン酸塩を混和した。その結果、生成される粒子のサイズとその表面の陰電荷が共に増加した。このようにICG、リポソーム、フィチン酸塩を構成要素とした新規トレーサーがマウスのリンパ節内に滞留する時間を評価した。その結果、対照のトレーサー(ICGおよびリポソーム封入ICG)と比較して最も良好な滞留性を発揮した。その蛍光強度比は6時間かけて上昇し、次いで24時間かけて緩やかに低下していった。ブタで安全性評価を行ったが、本新規トレーサーを投与しても死亡または体重減少は発生しなかった。ICGのみ投与した場合との明確な違いも示されず、全安全性は良好であった。本新規トレーサーは、後腹膜アプローチのためリンパ節を同定する時間が必要になる婦人科癌で有用なものになると考えられた。

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Cancer Science  

Indocyanine green (ICG) with near-infrared (NIR) fluorescence imaging is used for lymphatic mapping. However, binding of ICG to blood proteins like serum albumin can shorten its retention time in sentinel lymph nodes (SLNs). Here, we investigated the efficacy and safety of a new fluorescence tracer comprising phytate and liposome (LP)-encapsulated ICG. Coadministration of phytate with LP containing phosphatidic acid promotes chelation mediated by Ca2+ in bodily fluids to enhance SLN retention. Uniformly sized LPs (100 nm) encapsulating ICG under conditions that minimized fluorescence self-quenching during storage were produced. We analyzed the behavior of the new tracer (ICG-phytate-LP) and control tracers (ICG and ICG-LP) in the lymphatic flow of mice in terms of lymph node retention time. We also tested lymphatic flow and safety in pigs that have a more human-like lymphatic system. LPs encapsulating stabilized ICG were successfully prepared. Mixing LP with phytate in the presence of Ca2+ increased both the particle size and negative surface charge. In mice, ICG-phytate-LP had the best lymph node retention, with a fluorescence intensity ratio that increased over 6 h and then decreased slowly over the next 24 h. In pigs, administration of ICG and ICG-phytate-LP resulted in no death or weight loss. There were no obvious differences between blood test results for the ICG and ICG-phytate-LP groups, and the overall safety was good. ICG-phytate-LP may be a useful new tracer for gynecological cancers that require time for lymph node identification due to a retroperitoneal approach.

DOI： 10.1111/cas.15927

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記述言語：英語   出版者・発行元：Springer  

It can be difficult to distinguish an interstitial pregnancy from an angular pregnancy because of the close proximity of the implantation sites. The difference in pregnancy outcomes between interstitial and angular pregnancies makes this distinction very important. A 39-year-old gravida 7 para 4 who had undergone a laparoscopic right salpingo-oophorectomy (RSO) one year ago and a pregnancy termination via dilation and curettage (D&C) three weeks ago was suspected to have a ruptured right interstitial or angular pregnancy. The patient underwent a laparoscopic total hysterectomy. The postoperative histologic diagnosis was an abortion of a right angular pregnancy. Indeed, it is essential to rule out an interstitial or angular pregnancy during adnexal surgery, even soon after elective abortion. Proper management of an angular pregnancy could prevent a fatal outcome following a rupture or massive hemorrhage.

CiNii Research

記述言語：英語  

It can be difficult to distinguish an interstitial pregnancy from an angular pregnancy because of the close proximity of the implantation sites. The difference in pregnancy outcomes between interstitial and angular pregnancies makes this distinction very important. A 39-year-old gravida 7 para 4 who had undergone a laparoscopic right salpingo-oophorectomy (RSO) one year ago and a pregnancy termination via dilation and curettage (D&C) three weeks ago was suspected to have a ruptured right interstitial or angular pregnancy. The patient underwent a laparoscopic total hysterectomy. The postoperative histologic diagnosis was an abortion of a right angular pregnancy. Indeed, it is essential to rule out an interstitial or angular pregnancy during adnexal surgery, even soon after elective abortion. Proper management of an angular pregnancy could prevent a fatal outcome following a rupture or massive hemorrhage.

DOI： 10.7759/cureus.46171

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：American Journal of Clinical Oncology: Cancer Clinical Trials  

Objective: The aim of this study was to evaluate the progression-free survival (PFS) and overall response rate (ORR) of patients with recurrent endometrial cancer (REC) or advanced endometrial cancer (AEC) retreated with platinum-containing chemotherapy (PCC) based on the platinum-free interval (PFI). We compared our results with those reported in the KEYNOTE-775 study (that used pembrolizumab plus lenvatinib). Methods: A retrospective analysis was conducted of 65 patients with REC or AEC retreated with PCC between 2005 and 2020 at our hospital. Various clinicopathologic variables were analyzed: (1) age, (2) performance status, (3) histology, (4) history of pelvic irradiation in the adjuvant setting, (5) PFI, (6) chemotherapy regimen, (7) PFS and overall survival after retreatment with PCC, and (8) best ORR. Survival analyses were performed using Kaplan-Meier curves and log-rank tests. Results: The best ORR and PFS were 43.3% and 9.5 months, respectively, in patients with REC/AEC with a PFI ≥6 months. These results were comparable with those of patients treated with pembrolizumab and lenvatinib. The best ORR and PFS of patients with a PFI of <6 months appeared to be inferior to those of patients treated with pembrolizumab plus lenvatinib. Conclusions: Pembrolizumab plus lenvatinib seems to be a better treatment choice for patients with REC or AEC with a PFI of <6 months. For a PFI of ≥6 months, pembrolizumab plus lenvatinib or PCC can be used depending on the degree of residual side -effects associated with cytotoxic agents.

DOI： 10.1097/COC.0000000000001021

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DOI： 10.3390/reports6020018

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出版者・発行元：診断と治療社  

DOI： 10.34433/og.0000000065

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記述言語：日本語   出版者・発行元：福岡産科婦人科学会  

症例は76歳、3妊3産。不正性器出血を主訴に前医を受診し、子宮内膜肥厚を認め、精査加療目的に当科を紹介受診した。当科の子宮内膜全面掻爬にて子宮内膜異型増殖症の診断で、全腹腔鏡下単純子宮全摘出術+両側付属器摘出術を施行した。最終診断は子宮体癌IA期、類内膜癌G1の診断で、再発低リスク群であり、追加治療は施行せず経過観察とした。2年後の造影CT検査で大網左側に結節状の軟部陰影と周囲脂肪織混濁を認め再発が疑われた。CTガイド下生検を施行し、病理組織検査で非特異的な炎症所見を認めるのみで、悪性所見は認めなかった。更に1年後のCTで軟部陰影は増大傾向であり、子宮体癌再発の可能性も否定できず、診断確定目的に大網部分切除術を施行した。最終病理組織診断の結果は放線菌症の診断であった。放線菌症は悪性腫瘍との鑑別が難しいため、非典型的な臨床経過の場合は放線菌感染も鑑別の一つとして念頭においておくべきと思われた。(著者抄録)

CiNii Research

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Obstetrics and Gynaecology Research  

Aim: Westernization of lifestyle has increased the numbers of patients with endometrial cancer and obesity. This study aimed to compare the clinical outcomes of robotic-assisted surgery according to whether patients are obese, morbidly obese, or nonobese. Methods: Sixty-three patients with endometrial cancer who underwent robotic-assisted surgery between March 2014 and June 2022 were categorized according to whether they had a body mass index (BMI) <30 (group A, nonobese, n = 40), ≥30 and <35 (group B, obese, n = 13), or ≥35 (group C, morbidly obese, n = 10). Operation time, blood loss, perioperative complications, and recurrence rate were investigated. Results: Conversion to laparotomy was required in one case in group A and one in group C. There was no difference in total operation time, time for setting (including trocar installation and docking of the da Vinci robot), console time, or time for wound closure between the groups; however, there was a significant between-group difference in the total time for setting and wound closure. There was no significant difference in blood loss or complications between the groups. Three patients in group A and two in group B received adjuvant treatment; none have shown evidence of recurrent disease during a mean observation time of 21 months (range, 2–29). Two cases in group A and one in group B had recurrence during a mean observation time of 38 months (range, 19–46). Conclusion: Patients with endometrial cancer who are obese can be treated safely by robotic-assisted surgery with a low risk of complications and few relapses.

DOI： 10.1111/jog.15434

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記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

ロボット支援手術が施行された子宮内膜癌患者63例を対象とした後向きコホート研究を実施し、肥満がロボット支援手術の安全性および質に及ぼす影響について検討した。患者を非肥満群40例(BMI:30未満、中央値54歳)、肥満群13例(BMI:30以上35未満、中央値54歳)、病的肥満10例(BMI;35以上、中央値50歳)に分類した。評価項目は手術時間、出血量、周術期合併症、再発率とした。その結果、開腹術への移行は非肥満群1例、病的肥満群1例であった。総手術時間、セッティング時間(トロッカー留置、ダヴィンチロボットドッキングを含む)、コンソール時間、創部閉鎖時間に群間差は認められなかったが、セッティングおよび創部閉鎖の合計時間に群間差が認められた。出血量や合併症には群間差が認められた。非肥満群3例、肥満群2例に対して、術後補助療法が実施されたが、平均観察期間21ヵ月において再発は認められなかった。非肥満群2例、肥満群1例が平均観察期間38ヵ月に再発していた。以上から、肥満を呈する子宮内膜癌患者に対するロボット支援手術の安全性が示された。

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Cancer Gene Therapy  

Dysregulated G protein-coupled receptor signaling is involved in the formation and progression of human cancers. The heterotrimeric G protein Gα13 is highly expressed in various cancers and regulates diverse cancer-related transcriptional networks and cellular functions by activating Rho. Herein, we demonstrate that increased expression of Gα13 promotes cell proliferation through activation of Rho and the transcription factor AP-1 in human endometrial cancer. Of interest, the RhoGTPase activating protein (RhoGAP), ARHGAP35 is frequently mutated in human endometrial cancers. Among the 509 endometrial cancer samples in The Cancer Genome Atlas database, 108 harbor 152 mutations at 126 different positions within ARHGAP35, representing a somatic mutation frequency of 20.2%. We evaluated the effect of 124 tumor-derived ARHGAP35 mutations on Gα13-mediated Rho and AP-1 activation. The RhoGAP activity of ARHGAP35 was impaired by 55 of 124 tumor-derived mutations, comprised of 23 nonsense, 15 frame-shift, 15 missense mutations, and two in-frame deletions. Considering that ARHGAP35 is mutated in >2% of all tumors, it ranks among the top 30 most significantly mutated genes in human cancer. Our data suggest potential roles of ARHGAP35 as an oncogenic driver gene, providing novel therapeutic opportunities for endometrial cancer.

DOI： 10.1038/s41417-022-00547-1

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記述言語：英語   出版者・発行元：(公社)宮崎県医師会  

動脈-腸管瘻は消化管出血の原因としてはまれであるが,初発症状が致死性の大量出血の場合もある緊急性の高い疾患である。症例は44歳,9妊7産,子宮頸癌IB3期(扁平上皮癌)に対して広汎子宮全摘出術,両側付属器摘出術,術後補助療法として同時化学放射線療法を施行した。治療終了6ヵ月後に骨盤内再発を認め,全身化学療法を施行したが奏効しなかった。MSI検査の結果,MSI-highであったためペムブロリズマブ療法を開始した。腫瘍の著明な縮小を認め,4コース後の治療効果判定はPRであった。ペムブロリズマブ療法4コース目day7,当科入院中に突然,多量の下血,意識レベルの低下を認めた。緊急造影CTの結果,左内腸骨動脈からS状結腸への造影剤の漏出を認め,左内腸骨動脈-S状結腸瘻と診断した。直ちに左内腸骨動脈塞栓術を施行し止血した。発症から止血まで3時間の間に赤血球32単位,新鮮凍結血漿28単位,血小板10単位の輸血を要した。(著者抄録)

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Taiwanese Journal of Obstetrics and Gynecology  

Objective: Recent randomized phase III trial has shown significant benefit in overall survival (OS) for patients with advanced cervical cancer by adding bevacizumab to conventional chemotherapy. The aim of this study was to evaluate the prognostic impact for Japanese recurrent, persistent, or metastatic cervical cancer patients where bevacizumab was added to paclitaxel plus carboplatin. Materials and methods: A retrospective analysis was performed on 90 patients with recurrent, persistent, or metastatic cervical cancer mainly treated by paclitaxel plus carboplatin between 2005 and 2019 at our hospital. Data for the following clinicopathological variables were analyzed: (1) bevacizumab use; (2) histology; (3) disease presentation; (4) performance status; (5) prior chemotherapy containing platinum agent; (6) pelvic disease; (7) prior pelvic radiotherapy; (8) location of target lesions. Survival analysis was performed using Kaplan–Meier curves, log-rank tests, Wilcoxon tests, and Cox proportional hazards models combined with propensity score matching. Results: Adding bevacizumab to paclitaxel plus carboplatin showed significantly increased complete response to compared with that of non-users. In a Cox regression hazard model, bevacizumab use tended to show better OS though without statistically significance. After propensity score matching, adding bevacizumab to paclitaxel plus carboplatin showed a significant better OS by univariate analysis using Wilcoxon test, not by log-rank test. Conclusion: Adding bevacizumab to paclitaxel plus carboplatin showed a limited prognostic impact for recurrent, persistent or advanced cervical cancer patients in the real world. Further effective second-line treatments are needed to prolong OS of patients with recurrent, persistent or advanced cervical cancer.

DOI： 10.1016/j.tjog.2022.06.005

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Oncology (Switzerland)  

Introduction: The prognostic significance of lymphovascular space invasion (LVSI) in stage IA endometrial cancer remains unclear. The aim of this study was to evaluate the clinical significance of LVSI in stage IA endometrial cancer. Methods: Clinical data of patients with stage IA endometrial cancer who underwent initial surgery at our institution between January 2008 and December 2018 were reviewed retrospectively. Information of patients, surgery, and characteristics of cancer were obtained from medical records and pathological reports. Results: Two hundred ninety-seven patients were enrolled in this study. With a median follow-up of 60 months, 15 patients experienced recurrence (5.1%) and 4 patients died of endometrial cancer (1.3%). The recurrence and mortality rates did not differ significantly between the LVSI-positive and-negative groups (p = 0.07 and p = 0.41, respectively). Recurrence-free survival and endometrial cancer-specific survival also did not differ significantly between these groups (p = 0.11 and p = 0.49, respectively). The 5-year endometrial cancer-specific survival rates for tumors with and without LVSI were 97.0% and 98.9%, respectively. Among patients with low-grade tumors, recurrence-free survival and endometrial cancer-specific survival did not differ significantly between patients with tumors with and without LVSI (p = 0.92 and p = 0.72, respectively). The 5-year endometrial cancer-specific survival rates for low-grade tumors with and without LVSI were 100% and 99.3%, respectively. Conclusion: LVSI was not a prognostic factor of not only stage IA endometrial cancer but also stage IA low-grade cancer.

DOI： 10.1159/000521382

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Gynecologic Oncology  

Objective: Sentinel node biopsy alone (SNB) reduces the postoperative complications of pelvic lymphadenectomy, such as lymphedema and lymphangitis; however, the long-term prognosis after SNB is unclear. The objective of this study was to evaluate the long-term outcome and complications of patients with early-stage cervical cancer who underwent SNB for hysterectomy or trachelectomy. Methods: We performed SNB for cervical cancer using a radioisotope method in 181 patients between 2009 and 2017. If the intraoperative sentinel lymph node evaluation was negative for metastasis, no further lymph nodes were removed. Results: The median age of the patients was 34 years (range, 21–73 years). The International Federation of Gynecology and Obstetrics 2008 stage was IA1 in 6 patients, IA2 in 18, IB1 in 154, and IIA1 in 3. Of the 181 patients (44 with hysterectomy, 137 with trachelectomy), 8 did not undergo pelvic lymphadenectomy because of a false-negative intraoperative diagnosis, 20 received adjuvant therapy after surgery, and 4 (2.2%) experienced recurrence over a median follow-up period of 83.5 months (range, 25–145 months). In the four recurrent cases, recurrence occurred in the pelvis, lung, and bone in one patient each, while the remaining patient developed pelvic and para-aortic lymph node metastases. Of these four patients, one died, and the remaining three are alive without disease after multidisciplinary therapy. The 5-year progression-free and overall survival rates were 98.8% and 99.4%, respectively. Postoperative complications, such as lymphedema, were very low rate. Conclusions: SNB for early-stage cervical cancer might be safe and effective, with no increase in the recurrence and postoperative complications rate.

DOI： 10.1016/j.ygyno.2022.01.031

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/molehr/gaaa078

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41598-021-83200-5

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s12885-021-07875-9

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.ajpath.2017.11.008

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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5月

記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：仙台   国名：日本国  

開催年月日： 2017年11月 - 2017年12月

記述言語：英語  

開催地：Tokyo   国名：日本国  

開催年月日： 2017年11月

記述言語：日本語  

開催地：福岡   国名：日本国  

開催年月日： 2016年10月

記述言語：英語  

開催地：横浜   国名：日本国  

開催年月日： 2016年7月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：九州大学医学部百年記念講堂   国名：日本国  

部位特異的なDNAメチル化とゲノムワイドなDNA脱メチル化といったDNAメチル化状態の変化は、癌細胞に特徴的なエピジェネティクスの一つである。部位特異的なDNAメチル化が癌抑制遺伝子のサイレンシングと関連付けられて精力的に研究されてきたのに対し、ゲノムワイドな脱メチル化に関する研究はこれまで断片的であり、そのメカニズム、生理学的意義について未だ十分に研究されていない。われわれは、癌を引き起こす変異タンパク質BRAFV600Eのノックインマウスを用い、正常細胞にBRAFV600Eを発現させるだけでゲノムワイドなDNAの脱メチル化が誘導されることを見出した。この脱メチル化はDNA脱メチル化酵素TET3により引き起こされ、正常細胞ではユビキチンリガーゼSCFFBXW7によりTET3タンパク質は低レベルに制御されているが、BRAFV600EはTET3タンパク質のユビキチン化依存的分解を抑制するため、ゲノムワイドなDNA脱メチル化が促進されることを明らかにした。実際にBRAFV600Eの変異を有するヒト大腸ポリープにおいてもTET3タンパク質が異常蓄積しており、さらにBRAFV600Eノックインマウスにおける造腫瘍能はTET3ノックダウンにより抑制されることが分かった。KRASG12Dノックインマウスを用いても同様の実験結果を得ており、癌遺伝子BRAF、KRASが活性化するとTET3タンパク質の異常蓄積を介してゲノムワイドなDNA脱メチル化が誘導され、これが早期の腫瘍形成に重要な惑割を果たしていることが明らかとなった。

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