胆固醇代谢介导结肠癌突破“接触抑制”的新机制及其在靶向代谢治疗中的意义

正常细胞的“接触抑制”现象维持了组织器官的正常形态。肿瘤细胞的重要特征是“接触抑制”缺失导致的持续增殖。因此阐明肿瘤突破“接触抑制”的机制对理解肿瘤发生发展的机理乃至治疗的重要性不言而喻。Hippo通路激活导致的YAP失活和降解在正常细胞“接触抑制”中发挥了关键作用。课题组在前期研究中意外发现肠癌细胞“紧密接触”后游离胆固醇含量明显增多，而游离胆固醇能够通过激活非经典Wnt/PCP通路直接上调YAP表达。据此我们提出假设：肠癌细胞“紧密接触”导致细胞内游离胆固醇含量上调，后者维持了YAP表达和活性，从而介导了结肠癌细胞对“接触抑制”的抵抗。本研究拟通过脂质组学、基因敲减等体内体外实验，系统阐明肠癌细胞“紧密接触”后胆固醇代谢的变化及其对Hippo/YAP通路调控过程在结肠癌克服“接触抑制”中的作用，寻找该过程中起关键作用的分子靶点，为探索结肠癌靶向胆固醇代谢治疗提供新的策略。

"Contact inhibition" in normal cells maintains the normal morphology of tissues and organs. The major hallmark of cancer is the persistent abnormal proliferation caused by the loss of "contact inhibition". Therefore, elucidating the new mechanism by which colon cancer cells overcome "contact inhibition" would be of great significance in understanding tumorgenesis, tumor development and therapeutics. Inactivation of YAP in normal cells induced by Hippo pathway plays a key role in "contact inhibition". In the preliminary work, we found that intensive contact of colon cancer cells could elevate the free cholesterol level, and the cholesterol can directly up-regulate YAP expression by activating the non-classical Wnt/PCP pathway. Based on these observations, we raised a presumption: the elevated free cholesterol after cell close contact maintains the YAP level and activity, mediating the resistance to "contact inhibition" in colon cancer. This study intends to elucidate the changes of cholesterol metabolism after cell contact and its implications in the Hippo/YAP pathway and “contact inhibition”. The project would try to figure out the key molecules in this process and explore the new therapeutic strategies for cholesterol metabolism targeted therapy in colon cancer.