| Project/Area Number |
17K15627
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Pathological medical chemistry
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| Research Institution | Nippon Medical School |
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Principal Investigator |
iwabuchi chisato 日本医科大学, 大学院医学研究科, 研究生 (20514441)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2019: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | HIF-1a / 肺癌 / 薬剤耐性 / 肺がん / オートファジー / HIF1a / 癌幹細胞 / 癌 / 幹細胞 |
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| Outline of Final Research Achievements |
Gefitinib is specific inhibitor of EGFR-TKIs, have been found to be highly effective against the EGFR-positive NSCLC. However, many patients have resistance to gefitinib. We found that HIF1a is degraded by gefitinib at NSCLC cell lines and gefitinib degraded HIF1a in VHL-independent manner. We investigated why is HIF1a degraded by gefitinib and why is HIF1a-overexpression cell showed gefitinib-resistance. We made HIF1a-overexpression cell(RGWT), HIF1a-transcriptional inactive cell(RG803).
As a result, RGWT cell shows high resistance to gefitinib. We assessed tumorigenesis of RGWT and RG803 cell. RGWT promoted tumor growth significantly, whereas RG803 delayed tumor growth. These results suggest that transcriptional activity of HIF1a is key factor in tumor growth. The degradation of HIF1a was inhibited by Bafilomycin, and HIF1a bound to LAMP2A which were key factor of Chaperon-Mediated Autophagy (CMA). Therefore, gefitinib might induced CMA, and degraded HIF1a in VHL-independent manner.
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| Academic Significance and Societal Importance of the Research Achievements |
申請者が見出した、HIF-1aの転写活性を抑制することで再発した腫瘍の増殖が遅延することは今後の薬剤耐性解除の機構解析において重要は情報になると思われる。さらにゲフィチニブがオートファジー(CMA )を誘導し、それによりHIF-1aが分解されることは本研究で初めて示されたことである。これにより薬剤耐性を獲得している細胞群についてCMAを活性化することによりHIF-1aの分解を促進し薬剤耐性を解除できる可能性が示された。以上のことから、今後のEGFR陽性NSCLC治療において新たな選択肢の候補が示され、患者のQOL向上に非常に有用であると考えられる。
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