LRG1在BMP2诱导大肠癌发生EMT中的作用及机制研究

Epithelial-mesenchymal transtition(EMT) plays an indispensable role in metastasis of colorectal cancer(CRC). The molecular mechanisms and therapeutic targets of EMT have become research hotspots. As one inflammatory cytokine, bone morphogenetic protein 2(BMP2) is reported to have a dual role in both tumour metastasis and EMT. Interestingly, we have found that leucine-rich-alpha-2-glycoprotein 1(LRG1), the new protein associated with cancer and imflammation, could combine with BMP2, which resulted in enhancement both of mesenchymal markers and cell invasion. Hence, we will apply cellular and in-vivo assays to find out the following issues: (1)the mechanism of LRG1 to assist the complex formation of BMP2 and its receptors; (2)the mechanism of LRG1-induced EMT via Smad4-independent BMP signaling pathway; (3)the mechanism of LRG1-BMP2 combination to regulate EMT of CRC in vitro and in vivo. The study aims to provide key molecules as novel therapic targets for metastasis of colorectal cancer.

上皮-间质转化(EMT)是大肠癌转移的关键途径，其调控机制及治疗靶点已成为近年来的研究热点。据报道，骨形态形成蛋白2(BMP2)是一种与肿瘤转移相关的炎性因子，并且能够双向调控EMT。有趣的是，我们的前期研究发现：全新的肿瘤相关的炎性蛋白——富亮氨酸糖蛋白1 (LRG1)联合BMP2能使大肠癌细胞获得间质表型，并增强其侵袭能力。故本课题拟从细胞实验、临床标本和SCID小鼠原位移植人大肠癌转移模型等方面探讨：(1)LRG1为BMP2及其受体复合物提供结构框架的机制；(2)LRG1经非Smad4依赖的BMP信号通路启动EMT的机制；(3)LRG1联合BMP2在体内外调控大肠癌发生EMT的机制。本研究旨在发掘新的启动EMT的关键分子，为大肠癌转移的防治提供潜在的靶点。