Establishment of in vitro carcinogenesis model of endometriosis related ovarian carcinoma

• Project/Area Number: 15K10717
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Shimane University
• Principal Investigator: Nakayama Kentaro 島根大学, 医学部, 准教授 (70346401)
• Co-Investigator(Kenkyū-buntansha): 京 哲 島根大学, 医学部, 教授 (50272969)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 卵巣癌 / 明細胞癌 / ARID1A / 発癌 / 癌遺伝子 / 卵巣明細胞癌 / ARID１A / 子宮内膜症

Outline of Final Research Achievements

To clarify minimal requirement for carcinogenesis, we sought to establish an in vitro stepwise carcinogenesis model using immortalized endometriotic epithelial cells with overexpressed cyclinD1/cdk4 and hTERT, in which we additionally introduced selected genetic elements frequently observed in clinical samples. Mutational analysis using clinical samples of ovarian clear cell and endometrioid adenocarcinomas identified frequent ARID1A mutations (90%) and p53 mutations (20%), but their overlap was relatively rare. Thus, we introduced ARID1A knock out in combination with oncogenic mutant KRAS allele into immortalized cells, exhibit tumorigenic phenotypes. Additional introduction of genetic factors will be attempted to investigate in vitro and in vivo tumorigenicity, and c-Myc overexpression, mutant PIC3CA, or phosphorylated Akt (p-Akt) are going to transfect to immortalized endometriotic epithelial cells.

Research Products

• [Int'l Joint Research] University and Hospital Trust of Verona(Italy)
• [Journal Article] Affinity-purified DNA-based mutation profiles of endometriosis-related ovarian neoplasms in Japanese patients. (2018)
  • Author(s): Ishikawa M, Nakayama K, Nakamura K, Ono R, Sanuki K, Yamashita H1, Ishibashi T, Minamoto T, Iida K, Razia S, Ishikawa N, Kyo S.
  • Journal Title: Oncotarget Volume: 9 Pages: 14745-14763
  • Peer Reviewed / Open Access
• [Journal Article] Loss of beclin 1 expression in ovarian cancer: a potential biomarker to predict unfavorable outcome. (2018)
  • Author(s): Minamoto T, Nakayama K, Nakamura K, Katagiri H, Sultana R, Ishibashi T, Ishikawa M, Yamashita H, Sanuki K, Iida K, Nakayama S, Otsuki Y, Ishikawa N, Kyo S.
  • Journal Title: Oncol Lett Volume: 15 Pages: 1170-1176
  • DOI: 10.3892/ol.2017.7379
  • Peer Reviewed / Open Access
• [Journal Article] Microsatellite instability is a potential biomarker for immune checkpoint inhibitors in endometrial cancer. (2017)
  • Author(s): Yamashita H, Nakayama K, Ishikawa M, Nakamura K, Ishibashi T, Sanuki K, Ono R, Sasamori H, Minamoto T, Iida K, Sultana R, Ishikawa N, Kyo S.
  • Journal Title: Oncotarget Volume: 9 Issue: 5 Pages: 5642-5654
  • DOI: 10.18632/oncotarget.23790
  • Peer Reviewed / Open Access
• [Journal Article] Reconstitution of high-grade serous ovarian carcinoma from primary fallopian tube secretory epithelial cells (2017)
  • Author(s): Nakamura Kohei、Nakayama Kentaro、Ishikawa Noriyoshi、Ishikawa Masako、Sultana Razia、Kiyono Tohru、Kyo Satoru
  • Journal Title: Oncotarget Volume: 9 Issue: 16 Pages: 12609-12619
  • DOI: 10.18632/oncotarget.23035
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] NAC1/Gadd45GIP1 axis is related to cisplatin resistance through cellular senescence in ovarian cancer. (2017)
  • Author(s): Nakayama K, Rahman M, Rahman MT, Nakamura K, Sato E, Katagiri H, Ishibashi T, Ishikawa M, Iida K, Razia S, Ishikawa N, Kyo S
  • Journal Title: Oncol Lett. Volume: 13(6) Issue: 6 Pages: 4713-4719
  • DOI: 10.3892/ol.2017.6099
  • Peer Reviewed / Open Access
• [Journal Article] CCNE1 amplification is associated with aggressive potential in endometrioid endometrial carcinomas. (2016)
  • Author(s): Nakayama K, Rahman MT, Rahman M, Nakamura K, Ishikawa M, Katagiri H,
  • Journal Title: Int J Oncol. Volume: 48 Pages: 506-516
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] High pretreatment plasma D-dimer levels are related to shorter overall survival in endometrial carcinoma (2016)
  • Author(s): Nakamura K, Nakayama K, Ishikawa M, Katagiri H, Katagiri A, Ishibashi T,
  • Journal Title: Eur J Obstet Gynecol Reprod Biol. Volume: 201 Pages: 89-93
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Prognostic role and implications of mutation status of tumor suppressor gene ARID1A in cancer: a systematic review and meta-analysis. (2015)
  • Author(s): Luchini C, Veronese N, Solmi M, Cho H, Kim JH, Chou A, Gill AJ, Faraj SF, Chaux A, Netto GJ, Nakayama K, Kyo S, Lee SY, Kim DW, Yousef GM, Scorilas A, Nelson GS, Köbel M, Kalloger SE, Schaeffer DF, Yan HB, Liu F, Yokoyama Y, Zhang X, Pang D, Lichner Z, Sergi G, Manzato E, Capelli P, Wood LD, Scarpa A, Correll CU.
  • Journal Title: Oncotarget Volume: 36 Issue: 36 Pages: 39088-39097
  • DOI: 10.18632/oncotarget.5142
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Loss of autophagy-related protein Beclin 1 may define poor prognosis in ovarian clear cell carcinomas. (2015)
  • Author(s): Katagiri H, Nakayama K, Razia S, Nakamura K, Sato E, Ishibashi T, Ishikawa
  • Journal Title: Int J Oncol. Volume: 47 Issue: 6 Pages: 2037-2044
  • DOI: 10.3892/ijo.2015.3191
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Microsatellite instability is a potential biomarker for immune checkpoint inhibitor in endometrial cancer. (2017)
  • Author(s): Yamashita H, Nakayama K, Ishikawa M, Ishibashi T, Nakamura K, Sanuki K, Ono R, Sasamori H, Minamoto T, Iida K, Sultana R, Ishikawa N, Kyo S.
  • Organizer: AACR Annual Meeting 2017
  • Int'l Joint Research
• [Presentation] Successful reconstitution of high-grade serous ovarian carcinoma in vivo from primary fallopian tube secretory epithelial cells. (2017)
  • Author(s): Nakamura K, Nakayama K, Kiyono T, Ishikawa N, Minamoto T, Ishibashi T, Sanuki K, Yamashita H, Sasamori H, Sultana R, Ishikawa M, and Kyo S.
  • Organizer: AACR Annual Meeting 2017
  • Int'l Joint Research
• [Presentation] Exome sequencing in a dedifferentiated mucinous ovarian carcinoma (2017)
  • Author(s): Sanuki K, Nakayama K, Nakamura K, Minamoto T,Ishibashi T,Yamashita H, Ono R, Sasamori H, Razia S, Hossain M, Ishikawa M, Kyo S.
  • Organizer: AACR Annual Meeting 2017
  • Int'l Joint Research
• [Presentation] in vitro発癌モデルから見えてきた漿液性卵巣癌発生機構 (2016)
  • Author(s): 中山健太郎
  • Organizer: 第48回日本臨床分子形態学会
  • Place of Presentation: 熊本 くまもと県民交流館パレア
  • Year and Date: 2016-09-22
• [Presentation] Establishment of in vitro carcinogenic model of high-grade serous ovarian carcinoma using immortalized fallopian tubal secretory epithelial cell (2016)
  • Author(s): Nakamura K, Nakayama K, Kiyono T, Ishikawa N, Ishikawa M, Katagiri H, Minamoto T, Ishibashi T, Sato E, Sultana R, Iida K, Kyo S.
  • Organizer: 107th. American Association for Cancer Research, 2016
  • Place of Presentation: New Orelens, USA
  • Year and Date: 2016-04-16
  • Int'l Joint Research
• [Presentation] TypeⅠ. TypeⅡ漿液性卵巣癌のin vitro発癌モデルの構築～卵巣癌発生および、血管新生機構の解明にむけて～ (2015)
  • Author(s): 9.中山健太郎、中村康平、石橋朋佳、石川雅子、片桐 浩、佐藤絵美、スルタナラジア、飯田幸司、清野 透、京 哲
  • Organizer: 第57回日本婦人科腫瘍学会学術講演会
  • Place of Presentation: 盛岡 マリオス盛岡
  • Year and Date: 2015-08-07
• [Presentation] 分子標的治療、悪性腫瘍治療の新展開 (2015)
  • Author(s): 中山健太郎
  • Organizer: 第67回 日本産科婦人科学会学術講演会
  • Place of Presentation: 横浜 パシフィコ横浜
  • Year and Date: 2015-04-09
• [Book] 患者さんと家族のための子宮頚がん、体がん、卵巣がん治療ガイドラインの解説2016 (2016)
  • Author(s): 中山健太郎、その他
  • Total Pages: 250
  • Publisher: 金原出版
• [Book] 卵巣がん治療ガイドライン2015年版 (2015)
  • Author(s): 中山健太郎、その他
  • Total Pages: 198
  • Publisher: 金原出版
• [Remarks] 島根大学産婦人科 腫瘍研究室
  • URL: http://www.shimane-u-obgyn.jp/165.html