肝癌细胞中ChREBP与ERα相互作用的分子机制和功能研究

Liver cancer is closely related with metabolic syndrome and its regulation mechanism of metabolism is strongly focused in recent years. Our previous results showed that ChREBP is necessary in the metabolism and proliferation of liver cancer cells. We found that FLII is a transcriptional corepressor of ChREBP. It is reported that FLII is the transcriptional coactivator of estrogen receptorα (ERα). Our previous results demonstrated that ChREBP interacts with FLII and ERα, and ChREBP can inhibit the activity of ERα. We speculate that ERα may regulate the metabolism and proliferation of liver cancer cells through regulating the transcriptional activity of ChREBP.We will carry out the following research. Firstly, we will make clear the molecular mechanism of ChREBP interacts with ERα and whether its interaction is regulated by FLII. Secondly, we will figure out if ChREBP regulates the physiological function of ERα and the regulation is dependent on FLII or not. Last, we will study if and how ERα regulates the physiological function of ChREBP. These results will contribute to design molecular drug aimed to the interaction of ChREBP and ERα to regulate the metabolism and proliferation of liver cancer cells, and will provide a new molecular target for the therapy of liver cancer.

肝癌作为一种与代谢综合症密切相关的癌症，其代谢调控机制倍受关注。已知转录因子ChREBP为肝癌细胞代谢和增殖所必需，我们的前期工作显示FLII是ChREBP的转录共抑制因子。已知FLII是雌激素受体（ER）的转录共激活因子，我们发现ChREBP与FLII和ERα均存在相互作用并且ChREBP能抑制ERα的活性。我们推测ERα可能通过调控肝癌细胞中ChREBP的转录活性而调节肝癌细胞的代谢和增殖。本课题将深入研究：（1）ChREBP与ERα相互作用的分子机制，及FLII是否调控ChREBP与ERα的相互作用；（2） ChREBP是否及如何调控肝癌细胞中ERα的生理功能，此调控作用是否依赖FLII的存在；（3） ERα是否及如何调控肝癌细胞中ChREBP的生理功能。本研究结果将有助于设计针对ChREBP和ERα相互作用的分子药物来调节肝癌细胞代谢与增殖，从而为肝癌治疗提供新的分子靶点。

肝癌作为一种与代谢综合症密切相关的癌症，其代谢调控机制倍受关注。在本研究中我们得到如下结果。在肝癌细胞中，内源ERα和ChREBP存在相互作用，且存在免疫荧光共定位。ERα 截短体ERα-181-282、ERα-283-595和ChREBP免疫共沉淀。ChREBP 截短体ChREBP1-753与ERα免疫共沉淀。雌激素促进ERα的核定位，但不影响ChREBP的定位。当雌激素存在时，过表达ERα抑制ChREBP对下游靶基因ACC的转录激活，CHIP显示过表达ERα抑制ChREBP与其下游靶基因TXNIP和ACC的结合。与对照相比，ChREBP敲除的小鼠肝脏中ERα表达水平增加。HepG2细胞中过表达ERα且存在雌激素时，葡萄糖摄取减少，乳酸的生成减少，氧消耗量减少，细胞增殖减慢。已知ChREBPβ是ChREBPα的靶基因。我们发现共表达ERα和ChREBPα，ERα和ChREBPβ，并且存在雌激素时ChREBPβ启动子的转录活性降低并且此抑制作用可能是通过降低ChREBPα或ChREBPβ的蛋白水平实现。本研究结果不仅揭示了ERα和ChREBP相互作用的分子机制和生理意义，而且将为设计针对ChREBP和ERα相互作用的分子药物来调节肝癌细胞代谢与增殖提供新策略。