KIT信号分子在结直肠黏液性腺癌浸润与转移中的作用与机制研究

恶性肿瘤浸润和转移的发生机制仍不完全清楚，探究胚胎发育过程中细胞迁移的重要调控分子可为解析癌症的浸润和转移提供重要线索。已知原癌基因c-kit编码的KIT受体和ETV1分子功能障碍或丢失，可致胚胎发育中黑素细胞和原始生殖细胞的迁移受阻。我们最近的动物实验发现，结直肠黏液性腺癌高表达KIT和ETV4，且常见癌细胞浸润基膜、转移至黏膜下层等病理变化，但二者在该类肿瘤中的作用机制尚不明了。因此，本项目拟利用AOM和DSS制作野生型小鼠、KIT功能缺失小鼠、ETV4基因条件敲除小鼠的结直肠癌模型，结合临床结直肠癌患者手术标本，首先明确KIT和ETV4在结直肠癌的表达，继之，利用结直肠癌细胞系，结合多种抑制剂、RNAi基因敲降技术和慢病毒介导的基因过表达等手段，明确KIT-ETV4-MMPs/EMT信号分子轴在结直肠黏液性腺癌浸润和转移中的作用与机制，为临床寻找新的有效治疗靶点提供重要的实验依据。

The mechanisms of the invasion and metastasis of malignant tumors remain incompletely understood. Seeking for principal molecules regulating cell migration during embryonic development is a newly-developed insight into the invasion and metastasis of cancers. It is well known that KIT (encoded by proto-oncogene c-kit) and ETV1 deficits or loss-of-function hinder the outmigration of melanocytes and primordial germ cells. We recently demonstrated that in murine model, colorectal mucinous adenocarcinoma (CRMAC) that highly expressed KIT and ETV4 (a homology of ETV1) often extended beyond the base membrane of mucosa and invaded into submucosa. However, the role and mechanism of KIT and ETV4 in the invasion and metastasis of CRMAC is still not fully clarified. Therefore, in this study, we plan to establish AOM+DSS induced CRMAC murine model in wild type mice, KIT loss-of-function mice and ETV4 gene conditional knock-out mice in vivo, as well as collect clinic specimens from colorectal carcinoma resection, so as to identify the expressions of KIT and ETV4 in CRMAC. Moreover, the role and mechanism of KIT-ETV4-MMPs/EMT axis in the invasion and metastasis of CRMAC will be demonstrated in vitro by using corresponding inhibitors, RNAi techniques and lenti-virus mediated gene over-expression methods in colorectal cancer cell lines. Our results will provide an insight into looking for effective therapeutic targets in the treatment of CRMAC in clinic.