YAP/TAZ通过激活CCBE1基因转录促进结直肠癌淋巴管新生和淋巴结转移的研究

前期研究发现胚胎淋巴管发育的关键分泌蛋白CCBE1在结直肠癌中高表达，并促进结直肠癌淋巴管新生和淋巴结转移。同时CCBE1基因转录受TGFβ-SMADs通路负调控，但CCBE1在结直肠癌中转录激活的正调控机制尚不明确。Hippo通路下游的转录共激活子YAP/TAZ促进癌症发生、进展，但其在肿瘤淋巴管新生中的作用也不清楚。预实验结果表明结直肠癌细胞中YAP/TAZ可能通过激活CCBE1基因的转录表达，使癌细胞分泌物中CCBE1的水平上调，进而促进肿瘤微环境中淋巴管的新生和结直肠癌淋巴结转移。本项目拟从细胞、动物及临床三个层面探究结直肠癌中YAP/TAZ激活CCBE1基因转录的分子机制，阐明CCBE1介导的YAP/TAZ促进结直肠癌淋巴管新生及淋巴结转移的生物学功能。本研究将揭示结直肠癌中CCBE1转录失调以及Hippo信号通路失调促进淋巴结转移的新机制，为结直肠癌的临床诊断和治疗提供新靶点。

Our previous study showed that CCBE1, the key secreted protein in lymph vessel development, was highly expressed in colorectal cancer (CRC)，which enhanced tumor lymphangiogenesis and lymph node metastasis. The gene transcription of CCBE1 was inhibited by the TGFβ-SMADs pathway, but the regulatory mechanism of transcriptional activation of CCBE1 in CRC remains unknown. Transcriptional coactivators YAP/TAZ promote the oncogenesis and progression of a variety of cancers, but their roles in CRC lymphangiogenesis are unclear. Our primary studies indicated that YAP/TAZ could promote CRC lymphangiogenesis and lymph node metastasis by activating the transcription of CCBE1. Thus, we intend to explore the mechanism of the transcriptional regulation of CCBE1 by YAP/TAZ and elucidate the roles of YAP/TAZ in CRC lymphangiogenesis and lymph node metastasis from cell, animal and clinical levels. This study aims to reveal the new mechanism of CCBE1 transcription dysregulation and the role of Hippo signaling pathway in CRC lymph node metastasis, and provide new targets for the clinical diagnosis and therapy of CRC.