Induction of endometriotic cells by the upregulatory gene detected by the network analysis

• Project/Area Number: 19K09803
• 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: Yamaguchi University
• Principal Investigator: Maekawa Ryo 山口大学, 医学部附属病院, 講師 (90598749)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 子宮内膜症 / HOXC8 / 疾患上流遺伝子 / 卵巣チョコレート嚢胞 / HOCX8 / TGFベータ経路 / マスター遺伝子 / 数理モデル / 遺伝子制御ネットワーク

Outline of Research at the Start

本研究では、マスター遺伝子候補を子宮内膜間質細胞(ESC)で強制発現し、子宮内膜症に特徴的な細胞機能の変化や遺伝子の発現変化が誘導されるかを検討し、疾患発症のマスター遺伝子として機能しているかを検証する。

Outline of Final Research Achievements

The purpose of the study is to identify the upstream regulators (URs) involved in the onset and pathogenesis of ovarian endometrioma. We identified HOXC8 as a potential UR in ovarian endometrioma. HOXC8 overexpression significantly enhanced cell proliferation, migration, adhesion, and fibrotic activities, and altered expression statuses of the genes involved in transforming growth factor (TGF)-beta signaling. HOXC8 overexpression also increased the expression levels of phosphorylated SMAD2/SMAD3. The increased adhesion and fibrosis activities by HOXC8 were significantly inhibited by E-616452, a selective inhibitor of TGF-beta receptor type I kinases. Integrated genomic approaches identified HOXC8 as an UR in ovarian endometrioma. The pathological features of ovarian endometrioma including cell proliferation, adhesion, and fibrosis were induced by HOXC8 and its subsequent activation of TGF-beta signaling.

Academic Significance and Societal Importance of the Research Achievements

本研究において、疾患発症に重要な遺伝子としてHOXC8を同定し、HOXC8がTGFβシグナリングを活性化させて、増殖、浸潤、癒着、線維化能を実際に促進することを証明した。本研究により、根治的な治療法が存在しない子宮内膜症において、将来的にこの遺伝子を標的とした治療法の開発に発展する可能性がある。

Research Products

• [Journal Article] An Integrated Genomic Approach Identifies HOXC8 as an Upstream Regulator in Ovarian Endometrioma (2020)
  • Author(s): Yumiko Mihara, Ryo Maekawa, Shun Sato, Natsuko Shimizu, Yumiko Doi-Tanaka, Haruka Takagi, Yuichiro Shirafuta, Masahiro Shinagawa, Isao Tamura, Toshiaki Taketani, Hiroshi Tamura, Takeshi Abe, Yoshiyuki Asai, Norihiro Sugino
  • Journal Title: The Journal of Clinical Endocrinology & Metabolism Volume: 105 Issue: 12 Pages: 1-12
  • DOI: 10.1210/clinem/dgaa618
  • Peer Reviewed / Open Access