CHD1L调节肝癌干细胞干性及分化水平的作用机制研究

The prognosis of cancer patients is closely related to the level of tumor differentiation. Tumor cells usually have some similar characteristics as embryonic cells. According to the cancer stem cell (CSC) model, cancer originates from a subset of stem cells that have self-renewal properties. Differentiation arrest of stem cells or dedifferentiation of terminal differentiated cells gave rise to cancer. The stemness and differentiation of cancer is regulated by many factors, and the regulation at epigenetic level is of great importance. CHD1L is a well characterized oncogene which is frequently amplified in HCC. As chromosome remodelor, CHD1L regulates the expression of a series of genes and is closely related with tumor differentiation. This project will focus on the role of CHD1L in liver cancer stemness and differentiation. In vitro and in vivo experiments will be used to confirm the regulatory effect of CHD1L on liver cancer stem cells and their self-renewal ability. New technologies such as RNA-sequencing will further be used to elucidate the molecular mechanism. This project will also use animal model to evaluate the application of targeted inhibition of CHD1L in HCC treatment. And these may provide novel therapeutic target for clinical treatment of this deadly disease.

临床上肿瘤的预后与肿瘤的分化水平密切相关。肿瘤细胞常常表现出类似胚胎细胞的返祖特性。肿瘤干细胞模型认为肿瘤起源于组织器官内一群具有自我更新能力的干细胞。干细胞的分化受阻或是末端分化细胞的去分化导致了肿瘤的发生。肿瘤干细胞的干性和分化水平受一系列因素的调控。其中表观遗传水平的调控是一个重要环节。CHD1L是肝癌细胞中高度扩增的原癌基因。作为染色质重组蛋白，CHD1L参与调控了一系列基因的表达并与肝癌的分化水平密切相关。本项目将以肝细胞癌为模型，研究CHD1L调节肿瘤干细胞的干性及分化水平的分子机制。研究将通过体内和体外实验证明CHD1L对肝癌干细胞群体及其自我更新能力的影响，并进一步通过RNA-sequencing等技术阐明其作用的分子机制。同时，本项目还将通过动物模型探讨靶向性抑制CHD1L用于治疗肝癌的潜在应用价值。从而为肝癌的临床治疗提供新的更有效的治疗靶标。

肝细胞癌是人类常见的恶性肿瘤之一。由于肝癌的异质性及发病机理的复杂性，现有化疗药物及分子靶标药物治疗效果仍然有限。因此，对肝癌发病机理的进一步阐明，并寻找新的更有效的治疗靶标就非常必要。染色质结构重构蛋白CHD1L是我们实验室从肝癌高频扩增染色体区段1q21分离鉴定的重要原癌基因。我们前期的研究发现可以通过多条信号通路促进肝癌的起始及进展。在本项研究中我们发现CHD1L在肝脏发育过程中呈现动态表达。胚胎早期CHD1L高表达于肝脏起始细胞，随着肝细胞的分化成熟CHD1L表达逐渐降低乃至消失；肝癌细胞中CHD1L表达被重新激活，随着肝癌分化程度的降低其表达逐渐升高。免疫沉淀高通量测序配合生物信息学分析表明CHD1L可以转录激活一系列与胚胎发育分化相关的信号网络。作为染色质结构调控蛋白，CHD1L很可能通过打开局部染色质结构来激活发育相关转录因子如ESRRB，TCF4的表达，进而调控肝癌细胞的干细胞特性及分化水平。靶向抑制CHD1L可逆转肝癌的分化，并增加肿瘤对靶标药物索拉菲尼的敏感性。这一发现提出了通过靶向抑制染色质结构调控蛋白来诱导肝癌细胞分化并增强其对化疗药物的敏感性，这为肝癌治疗提供了新的策略。