2021 Fiscal Year Final Research Report
Specific mitochondrial electron transport chain processes involve oncogenesis of ovarian clear cell adenocarcinoma and can be targets of therapy
| Project/Area Number |
19K07446
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 49020:Human pathology-related
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| Research Institution | Teikyo University |
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Principal Investigator |
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Keywords | 卵巣 / 明細胞癌 / フェロトーシス / cystathionineγ-lyase / GPx4 |
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| Outline of Final Research Achievements |
We analysed expression of ferrotosis-resistant factors in ovarian clear cell carcinoma by immunohistochemistry and found that 2 ensymes; cystathionineγ-lyase (CTH) which are necessary for glutathione production, and glutathione peroxidase 4 (GPx4) which could restrain the oxidation of the cell membrane lipid, are overexpressed. We also found that inactivation of KEAP1 gne, associated with probably due to methylation of its promoter region and/or missense mutaion of its coding region, participated in overexpression of CTH, Administration of inhibitors for cystine transporter, an irreversible inhibitor of CTH, and inhibitor of GPx4 induced oxidation of the cell membrane lipid and reduded the tumor cell proliferation.
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| Free Research Field |
病理学
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| Academic Significance and Societal Importance of the Research Achievements |
卵巣明細胞癌においてはGST依存性のフェロトーシス耐性が亢進しており，その要因としてGSTの合成に必要なCTH，GSTを基質として細胞膜脂質の酸化を抑制し得るGPx4の発現が亢進していることが示唆された．明細胞腺癌は化学療法に対する感受性が低く進行例の予後は不良であり，標準化学療法であるTC療法との組み合わせを含めた分子標的治療の有用性の検証が求められている．本研究の内容は卵巣明細胞癌の特異的な生物学的特徴である内膜症性嚢胞由来，酸化ストレス耐性，化学療法抵抗性の裏付けとなるものであり，従来の化学療法とフェロトーシス耐性因子阻害剤の併用投与の有用性を示唆するものと考える．
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