2022 Fiscal Year Final Research Report
Elucidation of lncRNA functioning in both cancer and human stem cells, and its role in refractory cancer
| Project/Area Number |
20K07561
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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 50010:Tumor biology-related
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| Research Institution | Chiba University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
田中 知明 千葉大学, 大学院医学研究院, 教授 (50447299)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Keywords | 難治癌 / ヒト幹細胞 / lncRNA / scRNA-seq / RNA-seq / Proteome / エピジェネティクス |
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| Outline of Final Research Achievements |
The tumor suppressor p53 is activated by genotoxic stresses and affects multiple cellular functions, including differentiation. Here, we found human embryonic stem cells (hESCs) occurred in genotoxic stress-induced maldifferentiation via uncharacterized p53-induced lncRNA, lnc-p53. scRNA-seq revealed that lnc-p53 suppressed essential stemness genes and enhanced TGF-β signaling, promoting stem cell differentiation into fibroblast-like cells. The induction of lnc-p53 protected against DNA damage in hESCs by binding DNA-PKCs and attenuating its expression. Moreover, lnc-p53 expression was increased in multiple cancer tissue types, and this upregulation was linked to poor overall survival in several cancers, such as COAD, KIRC and PCPG. Together, these results suggest that p53-induced lnc-p53 not only suppresses hESC stemness but may confer tumor resistance to genotoxic stress by attenuating DNA damage signaling. Also, lnc-p53 might be novel target of cancer treatment and diagnostics.
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| Free Research Field |
lncRNA がん ヒト幹細胞 エピジェネティクス
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| Academic Significance and Societal Importance of the Research Achievements |
本研究は機能が全く明らかにされていない新規lncRNA “lnc-p53”を発見しただけでなく、lnc-p53がhESCで未分化性の抑制、線維芽様細胞への強制分化、Genotoxic stress耐性能の獲得など、多様な機能を持つことを明らかにした。加えてlnc-p53は様々ながん種で高発現し、抗がん剤耐性に寄与していることを証明した。興味深いことにlnc-p53はhESC並びにがん以外の正常細胞ではほとんど発現していないことから、核酸医薬の有力な標的となりえる。今後、本研究をさらに発展させ、lnc-p53に対する核酸医薬が抗がん剤耐性を示す難治がんに対する新規抗がん剤となるか検証を行う。
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