Impaired hypoxia-induced mitochondrial sleep may increase malignant behavior of gastric cancer cells

Research Project

Project/Area Number	18K08650
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Review Section	Basic Section 55020:Digestive surgery-related
Research Institution	Saga University
Principal Investigator	Kitajima Yoshihiko 佐賀大学, 医学部, 客員研究員 (30234256)
Co-Investigator(Kenkyū-buntansha)	田中智和佐賀大学, 医学部, 助教 (60781903) 能城浩和佐賀大学, 医学部, 教授 (90301340)
Project Period (FY)	2018-04-01 – 2021-03-31
Project Status	Completed (Fiscal Year 2020)
Budget Amount *help	¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000) Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000) Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000) Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords	HIF-1 / ROS / mieap / MALM / MMP-1 / hypoxia / 癌浸潤 / 低酸素 / Mieap / ミトコンドリア休眠 / 低酸素環境 / 活性酸素 / 胃癌
Outline of Final Research Achievements	In this study, we used two GC cell lines. 58As9 GC cells increased ROS accumulation and cancer invasion under hypoxia whereas MKN45 cells do not alter invasion or ROS accumulation. 2019:Mieap expression was observed in MKN45, but not in 58As9 cells. We demonstrated mieap plays a central role in controlling ROS production and cancer invasion in GC cells under hypoxia. We reported these evidences in Scientific Reports in 2020. 2020: Using iTRAQ technology, we tried to isolate mitochondria proteins, which is specifically expressed in MKN45, but not in 58As9. However we failed to isolate significant protein. 2021: In this year, we tried to isolate HIF-1 target gene, which is specifically expressed in 58As9 cells and contributes to hypoxia-induced cancer invasion. As a result, we demonstrated MMP-1 expression is a HIF-1 target and essential in hypoxia-induced cancer invasion in 58As9 cells.
Academic Significance and Societal Importance of the Research Achievements	本研究は、低酸素環境下にある固形癌では、MALMというミトコンドリア品質管理機構の破綻が契機となり、細胞内にROSが蓄積することで浸潤能が亢進し、癌悪性度を増強することを胃癌細胞株を用いて証明した。さらにmieapがMALM機序には必須な遺伝子であることも立証した。さらにこの低酸素下での胃癌細胞浸潤能亢進には、HIF-1ターゲット遺伝子であるMMP-1の低酸素発現誘導が重要であることも立証した。本研究は、生体内では低酸素環境下に置かれている固形癌の悪性度増強がmieap発現を基軸にしたMALMという新たな機序により惹起されることを初めて立証した。