转录因子TEAD1介导YAP1的促结直肠癌发展的分子机制研究

Hippo pathway is an important regulator of cell proliferation, growth and apoptosis. In colorectal cancer (CRC), dysregulation of Hippo pathway is closely associated with the progression of tumors via the activation of its downstream target YAP1. However, little is known about which oncogenic transcription factors are involved in the pathway. In our previous studies, we found that TEAD1 is the co-transcription factor of YAP1 in CRC, which is confirmed by TCGA analysis and luciferase reporter gene assay. The expression of TEAD1 is high in CRC, promotes tumor growth, and is associated with poor prognosis in patients with CRC. In this study, we will confirm the relationship between TEAD1 and YAP1 by ChIP-seq. We will also combined loss-of-function and gain-of-function studies with bioinformatics method to investigate the biological function of TEAD1 and its key downstream genes. The role of TEAD1 on YAP1-mediated progression of CRC will be studied in both in-vitro and in-vivo settings. The successful completion of this study will provide new insight of therapeutic targets to treat CRC.

Hippo通路是细胞增殖、生长和凋亡的重要调节器。在结直肠癌中，Hippo通路的失调可通过其下游关键效应蛋白YAP1导致肿瘤增殖，但关于YAP1是依赖于何种转录因子而发挥促癌作用却鲜有报道。我们前期通过TCGA数据库分析和荧光素酶报告基因实验证实：在结直肠癌中，转录因子TEAD家族中的TEAD1可能是YAP1结合的主要转录因子；TEAD1在结直肠癌中表达明显增高，促进肿瘤生长，且与病人的不良预后密切相关。因此，本研究将利用ChIP-seq等多种技术确认TEAD1和YAP1的关联性，并使用功能缺失、功能恢复实验等多种手段，结合生物信息学分析技术，在细胞水平和动物模型中进一步深入研究TEAD1在结直肠癌中的生物学功能并寻找其调控的关键靶基因，最终阐明TEAD1介导YAP1的促结直肠癌发展的分子机制，为结直肠癌的治疗提供新的研究思路和治疗靶点。

结肠癌是消化道常见恶性肿瘤之一，死亡率位居所有恶性肿瘤第3位，其中在很多患者晚期都会发生肝转移，是结直肠癌导致死亡的主要原因之一。尽管目前手术治疗、化疗等手段有了长足进步，但是结直肠癌肝转移患者的预后仍然不容乐观。因此筛选结肠癌肝转移的有效的诊治靶点具有很强的理论意义和应用价值。Hippo通路是细胞增殖、生长和凋亡的重要调节器。在结直肠癌中，Hippo通路的失调可通过其下游关键效应蛋白YAP1导致肿瘤增殖，但关于YAP1是依赖于何种转录因子而发挥促癌作用却鲜有报道。本课题发现了GPR4-YAP1轴在结肠癌组织中的表达显著升高，并通过生存分析，发现GPR4表达水平与结直肠患者的不良预后呈正相关。通过体内及体外实验，明确了GPR4-YAP1对于结直肠癌增殖以及侵袭转移的促进作用。进一步的机制研究提示GPR4被肿瘤微环境中的质子活化，激活下游的RHOA 及 HIPPO信号通路，从而促进结直肠癌的恶性生物学行为。总体而言，本研究揭示了GPR4-YAP1在结肠癌发生发展中的作用，为结肠癌的治疗提供了新的潜在靶点。