结直肠癌发生发展中HNF4蛋白与WNT/HIPPO信号通路双负反馈调节的机制研究

HNF4 (hepatocyte nuclear factor 4) is a member of the nuclear receptor superfamily and plays an important role in embryonic development, adult hepatocyte homeostasis and various tumorigenesis. However, its role in colorectal cancer remains unknown. Our previous study found and reported that HNF4 plays an important role in hepatocellular carcinoma. In this study, we found that abnormal expression of HNF4 is also found in the tissue of colorectal cancer. Further experiments confirmed that HNF4 competitively inhibited the WNT and HIPPO signaling pathways through the formation of HNF4-TCF4-TEAD4 complex in the nucleus in colorectal cancer. Meanwhile, both HNF4 gene transcription and protein levels are inhibited by the WNT and HIPPO signaling pathways respectively; and when the above-mentioned double negative feedback loop that maintains the homeostasis of the intestine undergoes abnormal destruction, it will promote the progression of colorectal cancer. In this proposal, we will systematically study the mechanism and function of HNF4 in regulating colorectal cancer, in molecular, cellular, transgenic /knockout mouse tumor models and clinical tumor sample levels. Our study will reveal a possibility that HNF4 may act as a novel target for diagnosis and treatment of colorectal cancer.

HNF4（肝细胞核因子4）是核受体超家族成员之一，在胚胎发育、成体肝细胞稳态以及多种肿瘤发生发展中发挥重要作用，然而在结直肠癌中的作用则相对空白。我们前期发现并报道过HNF4在肝癌中的重要调控作用，本课题在随后的研究中发现结直肠癌的病例组织中也存在HNF4表达的异常调控。进一步的实验证实，HNF4在结直肠癌中，通过细胞核内HNF4-TCF4-TEAD4三者蛋白复合体的形成，竞争性地抑制了WNT及HIPPO信号通路；同时，HNF4在基因转录和蛋白两个层面均受到WNT及HIPPO信号通路的抑制；当上述维持肠道组织稳态的双负反馈调节环的遭受异常破坏，将促进结直肠癌发展。本课题将从分子、细胞、原位肿瘤模型及基因修饰小鼠肿瘤模型并结合临床标本分析，系统研究HNF4在结直肠癌发生和发展过程中的作用及其相关的分子机理。同时，该研究将阐示HNF4在结直肠癌诊断和治疗的过程中成为潜在的新靶点。

WNT及HIPPO信号通路在维持肠道组织稳态中发挥关键作用，在结直肠癌转移过程中，二者信号异常激活导致结直肠癌进展，然而其抑制的调控因素依旧存在空白。HNF4（肝细胞核因子4）是核受体超家族成员之一，在胚胎发育、成体肝细胞稳态以及多种肿瘤发生发展中发挥重要作用。本项目以结直肠癌病例组织中HNF4的异常表达现象观察入手，通过细胞学及分子实验证实HNF4在细胞核内形成HNF4-TCF4-TEAD4三者蛋白复合体，竞争性地抑制了WNT及HIPPO信号通路；同时，HNF4在基因转录和蛋白两个层面均受到WNT及HIPPO信号通路的抑制；当上述维持肠道组织稳态的双负反馈调节环的遭受异常破坏，将促进结直肠癌发展。以上发现为结直肠癌的诊断与治疗提供新的思路的同时，也为结直肠癌标志物的开发积累了相应的理论和数据基础。