S100A4/non-muscle Myosin II Signaling Regulates Epithelial-Mesenchymal Transition and Stemness in Uterine Carcinosarcoma

• Project/Area Number: 17K08703
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human pathology
• Research Institution: Kitasato University
• Principal Investigator: Saegusa Makoto 北里大学, 医学部, 教授 (00265711)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 子宮癌肉腫 / S100A4 / ミオシン9 / 癌幹細胞 / 上皮間葉転換 / MYH9 / NMIIA / 子宮癌肉所 / Myosin / 癌・間質インターラクション / βーカテニン / 間質

Outline of Final Research Achievements

In this study, we investigated the role of S100A4 and related molecules in uterine cancer sarcoma (UCS). Cells overexpressing S100A4 had the characteristics of cancer stem cells (CSC), showing decreased cell proliferation and increased migration. This change disappeared by knockdown of S100A4. In shotgun proteomics analysis, S100A4 was closely associated with non-myocyte myosin II (NMII). Specific inhibition of NMII by brevistatin induced overexpression of S100A4 and induced fibroblast-like changes. From the above, in UCS, the S100A4 / NMII signaling pathway induces EMT / CSC and is involved in the derivation of sarcoma components from cancer components and changes in growth and migration ability.

Academic Significance and Societal Importance of the Research Achievements

極めて予後不良の子宮癌肉腫の発生の分子機構の１つにS100A4/NMIIA経路が関与することを立証したことに学術的意義がある。次のスッテプとして、この経路に対して抑制的に作用する小化学分子化合物を網羅的に検索して、子宮癌肉腫の新規治療法の開発に繋げることに社会的意義がある。

Research Products

• [Journal Article] Upregulation of fibronectin following loss of p53 function is a poor prognostic factor in ovarian carcinoma with a unique immunophenotype (2020)
  • Author(s): Yokoi Ako、Matsumoto Toshihide、Oguri Yasuko、Hasegawa Yoshinori、Tochimoto Masataka、Nakagawa Mayu、Saegusa Makoto
  • Journal Title: Cell Communication and Signaling Volume: 18 Issue: 1 Pages: 103-103
  • DOI: 10.1186/s12964-020-00580-3
  • Peer Reviewed / Open Access
• [Journal Article] S100A4/Nonmuscle Myosin IIA/p53 Axis Contributes to Aggressive Features in Ovarian High-Grade Serous Carcinoma (2020)
  • Author(s): Hiruta Ai、Oguri Yasuko、Yokoi Ako、Matsumoto Toshihide、Oda Yusuke、Tomohiro Mikihisa、Hashimura Miki、Jiang Zesong、Tochimoto Masataka、Nakagawa Mayu、Saegusa Makoto
  • Journal Title: The American Journal of Pathology Volume: 190 Issue: 11 Pages: 2304-2316
  • DOI: 10.1016/j.ajpath.2020.07.014
  • Peer Reviewed / Open Access
• [Presentation] 子宮癌肉腫のS100A4/非筋細胞ミオシンII系による肉腫成分誘導機構の解明 (2020)
  • Author(s): 栃本 昌孝, 三枝 信
  • Organizer: 第109回日本病理学会総会