Investigation of the significance of PPP2R1A mutation in endometrial carcinoma

• Project/Area Number: 18K09254
• 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: FUSEYA Chiho 信州大学, 医学部附属病院, 助教(診療) (50447736)
• Co-Investigator(Kenkyū-buntansha): 井田 耕一 信州大学, 医学部附属病院, 助教(診療) (10773442) ; 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: PIM1 / RPP2R1A / PP2A / 子宮内膜癌 / 子宮内膜漿液性癌 / リン酸化脱リン酸化 / PPP2R1A / 漿液腺癌 / PIM1阻害剤 / 漿液性癌 / リン酸化 / 脱リン酸化 / 脱リン酸化酵素複合体 / 癌肉腫

Outline of Final Research Achievements

PPP2R1A is a component of the PP2A complex, which dephosphorylates and represses oncogenes. PIM1 is an opposite factor of PP2A that phosphorylates target factors. We investigated the expression of PIM1 in endometrial carcinoma and found that PIM1 was strong in serous carcinoma (USC), with a significantly shorter overall survival in cases with high PIM1 expression. Suppression of PIM1 expression (PIM1-siRNA) reduced USC cell viability, migration, and invasion in vitro. Inhibition of PIM1 by PIM1 inhibitor (SGI-1776) also reduced cellular functions of USC cell lines. Oral administration with SGI-1776 significantly inhibited tumor growth in USC cell line ARK1 xenograft tumors transplanted subcutaneously in mice.

Academic Significance and Societal Importance of the Research Achievements

本研究成果はPPP2R1Aを含むPP2A複合体、および、それと拮抗的に作用するPIM1が子宮内膜癌の予後不良組織型である漿液性癌（SC）の悪性度上昇や予後に関連することを示した最初の報告であり、SCに対する新規治療につながる可能性がある意義を持つ。

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
• [Presentation] PIM1阻害薬は子宮内膜癌細胞の増殖を抑制する (2020)
  • Author(s): 竹内 穂高、宮本 強、浅香 亮一、小野 元紀、井田 耕一、田中 泰裕、山田 諭、小原 久典、塩沢 丹里
  • Organizer: 第72回日本産科婦人科学会学術講演会
• [Presentation] PIM1 is a potential therapeutic target for serous carcinoma of the endometrium (2020)
  • Author(s): Hodaka Takeuchi, Tsutomu Miyamoto, Ryoichi Asaka, Motoki Ono, Koichi Ida, Yasuhiro Tanaka, Manaka Shinagawa, Tanri Shiozawa
  • Organizer: 第79回日本癌学会学術講演会
• [Presentation] PIM1高発現は子宮内膜癌患者の予後不良を予測する因子になり得る (2019)
  • Author(s): 竹内穂高 宮本強 小野元紀 山田諭 井田耕一 et al.
  • Organizer: 第71回日本産科婦人科学会学術講演会