Estrogen regulates squamous metaplasia in the endometrial cancer

• Project/Area Number: 19K18691
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56040:Obstetrics and gynecology-related
• Research Institution: Kanazawa University
• Principal Investigator: Terakawa Jumpei 金沢大学, 学際科学実験センター, 助教 (90777731)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 子宮体癌 / 扁平上皮化生 / エストロゲン / マウスモデル / 細胞分化 / 動物モデル / PTEN

Outline of Research at the Start

子宮体癌において、癌進展に伴う扁平上皮化生の誘導が、PTEN欠損を有するヒト臨床検体とマウス病態モデルの両者に共通して認められる。本研究は、PTENを欠損した癌細胞では癌の進展を抑制する異方向への分化・成熟誘導機構が存在するとの新しい仮説に立脚し、 異方向分化を誘導する責任因子と機序の解明を目指す 。特に子宮特異的Pten欠損マウスを用いた解析より、濃度依存的なエストロゲンの作用が重要であることを見出したことから、エストロゲンの子宮体癌細胞に対する分子生物学的作用機序を明らかにする。

Outline of Final Research Achievements

Squamous metaplasia is found in both endometrial cancer patients and the mouse model which carries PTEN inactivation. We found that squamous metaplasia is developed in estrogen-dependent manner by the investigation of animal models. We further demonstrated that a small number of precursor cells which can differentiate into the stratified epithelium arises under the environment with existence of PTEN inactivated epithelial cells.

Academic Significance and Societal Importance of the Research Achievements

本研究では、子宮内膜においてPTENを欠損した上皮細胞が存在する環境下では本来の分化経路から逸脱した細胞集団が出現するという新しい知見を含んでおり、子宮体癌での微小環境変化を理解する上で重要な学術的意義があると考えられる。また、今後癌患者での病態解明や扁平上皮化生の誘導制御といった治療法開発にも結びつくと考えられる。

Research Products

• [Journal Article] Pillar[6]arene acts as a biosensor for quantitative detection of a vitamin metabolite in crude biological samples (2020)
  • Author(s): Ueno Masaya、Tomita Takuya、Arakawa Hiroshi、Kakuta Takahiro、Yamagishi Tada-aki、Terakawa Jumpei、Daikoku Takiko、Horike Shin-ichi、Si Sha、Kurayoshi Kenta、Ito Chiaki、Kasahara Atsuko、Tadokoro Yuko、Kobayashi Masahiko、Fukuwatari Tsutomu、Tamai Ikumi、Hirao Atsushi、Ogoshi Tomoki
  • Journal Title: Communications Chemistry Volume: 3 Issue: 1 Pages: 1-10
  • DOI: 10.1038/s42004-020-00430-w
  • NAID: 120006939157
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] SIX1 cooperates with RUNX1 and SMAD4 in cell fate commitment of Müllerian duct epithelium (2020)
  • Author(s): Jumpei Terakawa, Vanida A Serna, Devi M Nair, Shigeru Sato, Kiyoshi Kawakami, Sally Radovick, Pascal Maire, Takeshi Kurita
  • Journal Title: Cell Death and Differentiation Volume: 27 Issue: 12 Pages: 3307-3320
  • DOI: 10.1038/s41418-020-0579-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The lack of terminal tubule cells in the submandibular gland of mice deficient in submandibular gland protein C (2020)
  • Author(s): Nakata H, Terakawa J, Horike S, Daikoku T, Iseki S
  • Journal Title: Cell and Tissue Research Volume: 381(2) Issue: 2 Pages: 229-237
  • DOI: 10.1007/s00441-020-03205-w
  • Peer Reviewed / Open Access
• [Journal Article] IMP dehydrogenase-2 Drives Aberrant Nucleolar Activity and Promotes Tumorigenesis in Glioblastoma (2019)
  • Author(s): Kofuji S, Hirayama A, Eberhardt AO, Kawaguchi R, Sakamoto N, Kitahara S, Wolfe K, Lange L, Onishi N, Uematsu M, Saya H, Soga T, Grummt I, Bierhoff H, Sasaki AT.
  • Journal Title: Nat Cell Biol Volume: 21 Issue: 8 Pages: 1003-1014
  • DOI: 10.1038/s41556-019-0363-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Novel strategy of ovarian cancer implantation: Pre-invasive growth of fibrin-anchored cells with neovascularization. (2019)
  • Author(s): Matsuoka A, Mizumoto Y, Ono M, Kagami K, Obata T, Terakawa J, Maida Y, Nakamura M, Daikoku T, Fujiwara H.
  • Journal Title: Cancer Sci. Volume: 110 Issue: 8 Pages: 2658-2666
  • DOI: 10.1111/cas.14098
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] マウスモデルを用いた子宮がん発生を制御する分子機構の解明 (2019)
  • Author(s): 寺川 純平，井之上 幸範，松岡 歩，水本 泰成，藤原浩，大黒 多希子
  • Organizer: 第55回北陸生殖医学会
• [Book] Endometrial Gene Expression: An Emerging Paradigm for Reproductive Disorders (2020)
  • Author(s): Editors: Joanne Kwak-Kim
  • Total Pages: 220
  • Publisher: Springer Nature
  • ISBN: 9783030285838