STAT3/CDK6通路调控肝癌干细胞的静止期退出与自我更新的基础研究

Current treatment strategies of hepaticellular carcinoma focus on targeting liver cancer cells, and are lack of enough concern for liver cancer stem cells. Most liver cancer stem cells stay quiescent in cell cycle. However, it is not clear that how cancer stem cells regulate quiescent exit to make cells self-renewal and activation. Our previous findings reported that ① inhibition of STAT3 signaling by drug pimozide treatment reduced tumor cell proliferation, induced G0/G1 phase cell cycle arrest, as well as inhibited liver cancer stem cell self-renewal (Oncotarget, 2015; Int J Oncol, 2016), and that ② in the hepatic cancer stem cells STAT3 signaling activity is positively associated with CDK6 expression, since STAT3 can bind to the promoter region of CDK6 gene to promote transcription level (see section of research foundation). Therefore, we wil put forward the scientific hypothesis that STAT3/CDK6 signaling pathway plays role in regulating quiescent exit and self-renewal in liver cancer stem cells. This project will use the experimental method of molecular cell biology to complete the following studies: ① to confirm that in the hepatic cancer stem cells STAT3/CDK6 signaling pathway is involved; ② to describe the molecular mechanism that STAT3/CDK6 signaling pathway regulates quiescent exit and self-renewal in liver cancer stem cells; ③ to validate the signaling pathway in clinical samples. Finally, the project follows the principle of translational medicine to reveal that STAT3/CDK6 signaling pathway will be an important target for diagnosis and treatment of liver cancer, providing a basis for the development of drugs for targeting liver cancer stem cells.

原发性肝细胞癌的目前治疗策略多聚焦在肝癌细胞，而对肝癌干细胞的关注不足。肝癌干细胞大部分处于静止期，其如何从静止期退出而致细胞激活发挥自我更新的分子机制仍不清。基于前期工作的发现：①抑制STAT3信号下调肿瘤细胞的增殖并诱导静止期阻滞，抑制肝癌干细胞的自我更新（Oncotarget, 2015；Int J Oncol, 2016），②肝癌干细胞的STAT3活性与CDK6表达正相关，STAT3结合CDK6启动子区促使基因转录（见研究基础），因此提出假设STAT3/CDK6通路调控肝癌干细胞的静止期退出与自我更新。本项目将利用分子细胞生物学实验方法①确证肝癌干细胞存在STAT3/CDK6通路的分子机制；②阐述该通路调控肝癌干细胞的静止期退出与自我更新的作用机制；③采用临床标本进行验证。本项目遵循转化医学宗旨，揭示STAT3/CDK6通路将成为肝癌诊疗的重要靶点，为肝癌干细胞药物开发提供基础。

项目背景：原发性肝细胞癌的恶性程度极高、预后极差，数十年来在诊断、治疗的预后等各方面的进展十分有限，因此急需寻找一种新的更为有效的治疗方法提高肿瘤治疗效果。靶向肝癌干细胞能明显地提升肝癌的治疗效果。这急切需要对肝癌干细胞激活的分子机制深入研究。.研究内容：.1)研究在肝癌干细胞中STAT3信号与CDK6表达相关性分析；.2)研究在肝癌干细胞中STAT3信号通路调控CDK6的分子机制；.3)研究 STAT3/CDK6通路调控肝癌干细胞的静止期退出与自我更新；.4)研究CDK6基因表达在肝癌细胞中的临床意义；.5) 探讨了CDK6潜在抑制剂Costunolide和Pimozide在肝癌细胞防治的作用研究；.研究结果：.1)提出在肝癌干细胞中存在STAT3/CDK6通路的分子机制，STAT3信号的持续活化可直接结合到CDK6启动子上，从转录水平上调控CDK6表达；.2)阐述STAT3/CDK6通路对于肝癌干细胞的特性维持起着重要作用，能有效地调控肝癌干细胞的静止期退出与自我更新，使干细胞活化而加速肿瘤的恶化进程；.3)揭示STAT3/CDK6通路可作为肝癌疾病的诊断与治疗的重要靶点;.4)表明CDK6潜在抑制剂Costunolide和Pimozide在肝癌细胞防治的临床应用前景.科学意义：本研究有效地利用“转化医学”宗旨，发现生物学现象，揭示其分子机理和提出医学转化方案。本研究项目是追踪性创新，完善STAT3信号通路在肝癌发生发展及肝癌干细胞活化的分子机制；是国内外首次提出STAT3/CDK6通路在肝癌干细胞中静止期退出和自我更新的作用；揭示STAT3/CDK6通路将成为肝癌疾病诊疗的重要靶点，为肝癌干细胞药物开发提供重要的理论基础，将有望提高恶性肿瘤的临床治愈率。

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