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

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。

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.