| Project/Area Number |
15K08317
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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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| Research Field |
Pathological medical chemistry
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| Research Institution | Showa University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
柴沼 質子 昭和大学, 薬学部, 教授 (60245876)
石川 文博 昭和大学, 薬学部, 助教 (60515667)
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| Project Period (FY) |
2015-04-01 – 2018-03-31
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| Project Status |
Completed (Fiscal Year 2017)
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| Budget Amount *help |
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | MMP9 / ミトコンドリア / 活性酸素種 / NADPH oxidase 4 / MMP-9 / NOX4 / 活性酸素 |
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| Outline of Final Research Achievements |
Here, we report a molecular axis, comprising the molecular adaptor hydrogen peroxide-inducible clone-5 (HIC-5), NADPH oxidase 4 (NOX4), and mitochondrial reactive oxygen species (mtROS), that regulates MMP9 expression and may be a target to suppress cancer metastasis. We found that that this axis primarily down-regulates mtROS levels which stabilize MMP9 mRNA. Specifically, HIC-5 suppressed the expression of NOX4, the source of the mtROS, thereby decreasing mtROS levels and, consequently, destabilizing MMP9 mRNA. Interestingly, screening cancer cell lines suggests that this mechanism operates in cancer cells by expressing oncogenic RAS, implying an important role of HIC-5 in suppressing metastasis of activated RAS-driven tumors. Notably, HIC-5 knockdown promoted lung metastasis of MDA-MB-231 cancer cells in mice without affecting primary tumor growth. We conclude that NOX4-mediated mtROS signaling increases MMP9 mRNA stability and affects cancer invasiveness.
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