2019 Fiscal Year Final Research Report
Generation and maintenance mechanism of cancer stem cells in tumor microenvironment, involved in lung cancer development and reocurrence.
| Project/Area Number |
17H04054
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pathological medical chemistry
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| Research Institution | Nippon Medical School |
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Principal Investigator |
Tanaka Nobuyuki 日本医科大学, 大学院医学研究科, 大学院教授 (80222115)
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| Co-Investigator(Kenkyū-buntansha) |
清水 幹容 日本医科大学, 大学院医学研究科, ポストドクター (00774358)
弦間 昭彦 日本医科大学, 大学院医学研究科, 大学院教授 (20234651)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Keywords | がん幹細胞 / がん治療 / IL-8 / O-GlcNAcylation / GLI1 / MEP50 / PRMT5 / 薬剤スクリーニング |
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| Outline of Final Research Achievements |
Cancer stem cells (CSCs) are a subset of tumor cells that exhibit self-renewal ability and generate the diverse cells that comprise the tumor. CSCs show increased quiescence and poor responses to conventional chemotherapy. We found that IL-8 is overexpressed in lung cancer stem cells and is required for CSC properties, including tumor-initiating abilities. IL-8 stimulation of lung cancer cells induced glucose uptake, resulting in enhancement of protein O-GlcNAcylation, and these events were required for the generation and maintenance lung CSCs. Moreover, an O-GlcNAcylation inhibitor, OSMI1, reduced CSC number and tumor development in vivo. Together, these results reveal that IL-8-induced O-GlcNAcylation is required for generation and maintenance of CSCs of lung cancer cells. Moreover, we also found novel activation mechanism of transcription factor GLI1, critical regulator of stem cells, by the methylosome MEP50/PRMT5 complex in lung cancer cells.
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| Free Research Field |
分子生物学
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| Academic Significance and Societal Importance of the Research Achievements |
我々の研究から、炎症性ケモカインIL-8によるタンパクのO-GlcNAc修飾の増加が肺がんのがん幹細胞の発生と維持に重要であること、この機構ががん幹細胞の治療の有用な標的となることを見出した。また、がん幹細胞の発生と維持に重要でな転写因子GLI1のMEP50/PRMT5を介した新しい活性化機構を発見し、この機構が肺がんでも働いていることを見出した。この機構もがんの治療の標的として有効であると考えられ、現在GLI1とMEP50との結合を阻害する薬剤のスクリーニングを試みている。これらのことは、がん幹細胞の発生機構の解明と新たな肺がんの治療法の開発につながり、学術的・社会的意義が高いと考えている。
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