Clinical study of endometrial cancer prevention by metformin: targeting obesity and insulin resistance

• Project/Area Number: 15K10702
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Chiba University
• Principal Investigator: Mitsuhashi Akira 千葉大学, 大学院医学研究院, 准教授 (40302541)
• Co-Investigator(Kenkyū-buntansha): 生水 真紀夫 千葉大学, 大学院医学研究院, 教授 (30226302) ; 植原 貴史 国立研究開発法人国立がん研究センター, 中央病院, 医員 (70568659)
• 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: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 子宮体癌 / 肥満 / インスリン抵抗性 / メトホルミン

Outline of Final Research Achievements

bnormal glucose metabolism, insulin resistance, and obesity were found to be highly prevalent in patients with endometrial cancer and atypical endometrial hyperplasia. Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase that is associated with insulin resistance and type 2 diabetes. Preoperative metformin treatment significantly reduced PPP2R4 mRNA expression in endometrial cancer tissues and immunohistochemistry showed significantly decreased expression of the PP2A-β subunit. PPP2R4 knockdown reduced cell proliferation and induced apoptosis in HEC265 and HEC1b cells by activating caspases 3/7. Metformin inhibited the growth of endometrial cancer cells in vivo by indirectly down-regulating PP2A-β and PPP2R4. Inhibition of PP2A may become a preventive measure and a therapeutic strategy for endometrial cancer with insulin resistance.

Research Products

• [Journal Article] Antitumor effects of metformin via indirect inhibition of protein phosphatase 2A in patients with endometrial cancer. (2018)
  • Author(s): Hanawa S, Mitsuhashi A, Shozu M.
  • Journal Title: PLoS One Volume: 13 Issue: 2 Pages: e0192759-e0192759
  • DOI: 10.1371/journal.pone.0192759
  • Peer Reviewed / Open Access
• [Journal Article] Prospective evaluation of abnormal glucose metabolism and insulin resistance in patients with atypical endometrial hyperplasia and endometrial cancer. (2017)
  • Author(s): Mitsuhashi A, Uehara T, Hanawa S, Shozu M.
  • Journal Title: Support Care Cancer. Volume: 25 Issue: 5 Pages: 1495-1501
  • DOI: 10.1007/s00520-016-3554-y
  • Peer Reviewed
• [Journal Article] Metformin alters DNA methylation genome-wide via the H19/SAHH axis. (2017)
  • Author(s): Zhong T, Men Y, Lu L, Geng T, Zhou J, Mitsuhashi A, Shozu M, Maihle NJ, Carmichael GG, Taylor HS, Huang Y.
  • Journal Title: Oncogene Volume: 36 Issue: 17 Pages: 2345-2354
  • DOI: 10.1038/onc.2016.391
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Phase II study of medroxyprogesterone acetate plus metformin as a fertility-sparing treatment for atypical endometrial hyperplasia and endometrial cancer (2016)
  • Author(s): Mitsuhashi A
  • Journal Title: Ann Oncol Volume: 27 Issue: 2 Pages: 262-266
  • DOI: 10.1093/annonc/mdv539
  • Peer Reviewed
• [Journal Article] 特集/婦人科悪性腫瘍治療に対するドラッグリポジショニングの幕開け -既存薬に秘められた新たな可能性- 4.糖尿病治療薬メトホルミンが子宮体がんに奏効する可能性 (2015)
  • Author(s): 三橋 暁
  • Journal Title: 産科と婦人科 Volume: 82 Pages: 1099-1105
• [Presentation] Antitumor effects of metformin via indirect inhibition of protein phosphatase PP2A in patients with endometrial cancer (2016)
  • Author(s): Shinsuke Hanawa, Akira Mitsuhashi, Makio Shozu
  • Organizer: 16th Biennial Meeting of the International Gynecologic Cancer Society (IGCS)
  • Place of Presentation: Lisbon,Portugal
  • Year and Date: 2016-10-29
  • Int'l Joint Research
• [Presentation] 子宮体癌組織のPP2Aの発現はメトホルミン投与で抑制される (2016)
  • Author(s): 塙伸輔、三橋暁、生水真紀夫
  • Organizer: 日本婦人科腫瘍学会学術講演会
  • Place of Presentation: 米子コンベンションセンター（鳥取県米子市）
  • Year and Date: 2016-07-08
• [Presentation] メトホルミン投与はインスリン抵抗性を有する患者で子宮体癌組織のPP2A発現を抑制する (2016)
  • Author(s): 塙伸輔、三橋暁、生水真紀夫
  • Organizer: 日本産科婦人科学会学術講演会
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
  • Year and Date: 2016-04-21
• [Presentation] 子宮体癌に対するメドロキシプロゲステロン＋メトホルミン併用妊孕性温存療法の臨床第2相試験 (2016)
  • Author(s): 三橋暁、塙伸輔、碓井宏和、生水真紀夫
  • Organizer: 日本産科婦人科学会学術講演会
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
  • Year and Date: 2016-04-21
• [Presentation] 子宮体癌に対する メトホルミン療法の応用 (2016)
  • Author(s): 三橋 暁
  • Organizer: 第16回関東ホルモンと癌研究会
  • Place of Presentation: 東京大学医科学研究所附属病院（東京都港区)
  • Year and Date: 2016-01-30