转录因子HHEX调控YAP促进结直肠癌增殖转移的生物学功能和分子机制研究

转录因子HHEX是血液系统发育、分化的关键基因，结直肠癌发生进展中HHEX的作用和机制尚不明确。YAP在结直肠癌中mRNA高表达，与不良预后相关，但结直肠癌中YAP的转录激活机制以及YAP/TEAD转录蛋白复合体的调控机制也尚待深入研究。课题组前期研究发现，结直肠癌中HHEX高表达，促进肠癌细胞增殖、迁移，与肿瘤不良预后相关。结直肠癌中YAP可能是HHEX下游直接靶基因，同时发现HHEX分别与YAP和TEAD4结合形成HHEX-YAP-TEAD4蛋白复合体，可激活YAP/TEAD4的转录活性以及Hippo-YAP通路下游的靶基因，从而促进结直肠癌发生和恶性转化。本项目拟利用基因敲除小鼠模型，通过体外细胞功能与分子机制实验，结合临床组织验证，探讨转录因子HHEX通过调控Hippo-YAP信号通路促进结直肠癌增殖、转移的生物学功能和分子机制，为结直肠癌提供临床诊断分子标记物以及潜在治疗靶点。

Transcription factor HHEX is a key gene for the development and differentiation of the blood system. However, the role and mechanism of HHEX in the development of colorectal cancer is unknown. Overexpression of YAP in colorectal cancer is positively correlated with poor prognosis, but the mechanism of YAP transcriptional activation and the regulation of YAP/TEAD transcription complex in colorectal cancer need to be further studied. Previously, we found that overexpression of HHEX in colorectal cancer might promote the proliferation and migration of cancer cells and was associated with poor prognosis. YAP might be a direct target gene of HHEX in colorectal cancer. Furthermore, it was found that HHEX could combine with YAP and TEAD4 to form the HHEX-YAP-TEAD4 protein complex, which could activate the transcriptional activity of YAP/TEAD4 and target genes of the Hippo-YAP signaling pathway, thereby promoting the progress of colorectal cancer and malignant transformation. By using the knockout mouse model in vitro cell function experiments combined with clinical tissue verification our study intends to explore the biological function and molecular mechanism of HHEX in the development of colorectal cancer providing clinical diagnostic molecular markers and potential therapeutic targets for colorectal cancer.