The loss of Arid1a function on endometrial carcinogenesis and drug sensitivity

• Project/Area Number: 18K09255
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56040:Obstetrics and gynecology-related
• Research Institution: Shinshu University
• Principal Investigator: UCHIKAWA Junko 信州大学, 医学部, 助教(特定雇用) (00722927)
• Co-Investigator(Kenkyū-buntansha): 塩沢 丹里 信州大学, 学術研究院医学系, 教授 (20235493) ; 竹内 穂高 信州大学, 医学部附属病院, 助教(診療) (30816351) ; 宮本 強 信州大学, 学術研究院医学系, 准教授 (70418721)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: ARID1A / 子宮内膜癌 / 子宮内膜症 / 薬剤感受性 / マウスモデル / 異所性子宮内膜 / Arid1a

Outline of Final Research Achievements

We have established a mouse model capable of inducing gene knockout (KO) specifically in the endometrial epithelium. In this mouse model, Arid1a-KO did not change its phenotype, Pten-KO developed atypical hyperplasia after one week, and half of them became adenocarcinoma in about 6 to 8 weeks. In the double-KO of Arid1a and Pten, all cases became adenocarcinoma within ten days. Using this double-KO endometrial carcinoma mouse model, we examined the sensitivity of several drugs, including cisplatin, HDAC inhibitor/medroxyprogesterone acetate combination therapy, Niraparib, compound A, natural compound B. However, none of them were effective. We also established a mouse model that develops endometriotic cysts in the abdominal cavity of mice and succeeded in inducing carcinoma by inducing double-KO.

Academic Significance and Societal Importance of the Research Achievements

本研究によりARID1A機能欠失がAEHからEECへの進行を促進することが明らかとなった。EEC発癌マウスモデルは今後の薬物療法検討に役立つと考えられる。また、同様に子宮内膜症発癌マウスモデルは、子宮内膜症発癌研究や薬物療法研究に役立つ可能性が考えられる。

Research Products

• [Journal Article] Inactivation of Arid1a in the endometrium is associated with endometrioid tumorigenesis through transcriptional reprogramming (2020)
  • Author(s): Suryo Rahmanto Yohan、Shen Wenjing、Shi Xu、Chen Xi、Yu Yu、Yu Zheng-Cheng、Miyamoto Tsutomu、Lee Meng-Horng、Singh Vivek、Asaka Ryoichi、Shimberg Geoffrey、Vitolo Michele I.、Martin Stuart S.、Wirtz Denis、Drapkin Ronny、Xuan Jianhua、Wang Tian-Li、Shih Ie-Ming
  • Journal Title: Nature Communications Volume: 11 Issue: 1 Pages: 2717-2717
  • DOI: 10.1038/s41467-020-16416-0
  • Peer Reviewed
• [Journal Article] Loss of ARID1A expression in endometrial samplings is associated with the risk of endometrial carcinoma. (2018)
  • Author(s): Ting-Tai Yen, Tsutomu Miyamoto, Shiho Asaka, M. Herman Chuic, Yeh Wang, Shiou-Fu Lin, Rebecca L. Stone, Amanda N. Fader, Ryoichi Asaka, Hiroyasu Kashima, Tanri Shiozawa, Tian-Li Wang, Ie-Ming Shih, Edward J. Tanner III
  • Journal Title: Gynecologic Oncology Volume: 150 Issue: 3 Pages: 426-431
  • DOI: 10.1016/j.ygyno.2018.06.025
  • Peer Reviewed / Int'l Joint Research