2021 Fiscal Year Final Research Report

Search for new targets of endometriosis therapy based on gene expression profile by AI

Research Project

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Project/Area Number	19K22688
Research Category	Grant-in-Aid for Challenging Research (Exploratory)
Allocation Type	Multi-year Fund
Review Section	Medium-sized Section 56:Surgery related to the biological and sensory functions and related fields
Research Institution	Yamaguchi University
Principal Investigator	Sugino Norihiro 山口大学, 大学院医学系研究科, 教授 (10263782)
Co-Investigator(Kenkyū-buntansha)	浅井義之山口大学, 大学院医学系研究科, 教授 (00415639)
Project Period (FY)	2019-06-28 – 2022-03-31
Keywords	子宮内膜症 / 卵巣チョコレート嚢胞 / 遺伝子ネットワーク / バイオインフォマティクス / ブーリアンネットワーク / マスター遺伝子 / HOXC8 / TGF-β
Outline of Final Research Achievements	The study succeeded to identify the upstream regulators (URs) involved in the pathogenesis of ovarian endometrioma. An analytic method, SMITE was used with transcriptome data from ovarian endometrioma stromal cells (ovESCs) and eutopic endometrium stromal cells (euESCs) in combination with publicly available gene regulatory network data. Furthermore, Boolean network simulation confirmed that the 12 candidate genes chosen by SMITE are URs. One of the URs, HOXC8, was confirmed to be overexpressed in ovESCs. HOXC8 overexpression significantly enhanced cell proliferation, migration, adhesion, and fibrotic activities, and also activated the TGF-β signaling, which are pathological features of ovarian endometrioma. The increased adhesion and fibrosis activities by HOXC8 were significantly inhibited by E-616452, a selective inhibitor of TGF-β receptor. In conclusions, integrated genomic approaches identified HOXC8 as an UR in ovarian endometrioma.
Free Research Field	産婦人科
Academic Significance and Societal Importance of the Research Achievements	子宮内膜症（卵巣チョコレート嚢胞）の発症において鍵となるマスター遺伝子を同定することができ、将来的にそれらを標的とした分子標的治療の開発に役立つ可能性がある。また、バイオインフォマティクスと数理モデルを用いた本研究の研究手法は、疾患における複雑な発現制御ネットワークを明らかにする上で、今後、更に重要となる研究手法である。