肿瘤微环境中基质细胞高表达MLCK促进胃癌转移的机制研究

研究发现微环境中肿瘤细胞和基质细胞的相互作用对肿瘤进展发挥着重要作用。本课题组前期工作发现MLCK高表达于胃癌基质中，其表达量与胃癌临床分期和成纤维细胞活化等密切相关。因此我们通过模拟建立成纤维细胞依赖的胃癌微环境模型，探讨MLCK在胃癌转移中的作用及机制：1）首先分析MLCK在胃癌组织和基质成纤维细胞中表达，揭示MLCK与胃癌转移的相关性；2）通过RNAi或化学抑制剂下调CAF中MLCK表达和活性，阐明MLCK表达对胃癌细胞体内外转移能力的影响；3）通过高通量芯片筛查CAF中MLCK下调前后差异分子，探讨MLCK影响胃癌转移的分子机制；4）探讨胃癌微环境调控CAF中MLCK表达的分子机制。本课题以MLCK为切入点，从基因转录差异、蛋白表达调控以及系统生物学的层面，阐明它在胃癌微环境中炎症反应、胃癌细胞EMT及成纤维细胞活化相关的分子机制，为临床干预胃癌转移提供新的理论与实验依据。

Accumulating evidence has indicated that cancer progression is regulated by interactions between tumor cells and activated stromal cells. Our previous study found that MLCK was highly expressed on stromal cells of gastric cancer, and correlated with tumor stage and active phenotypes of fibroblasts. In the present study, we aim to remodel fibroblast-dependent tumor microenvironment and determine the role of MLCK in the metastasis of gastric cancer. Aim 1: To determine the relationship between MLCK expression in stromal cells and clinicopathological features of gastric cancer by analyzing the expression of MLCK in gastric cancer and stromal fibroblasts; Aim 2: To define the role of MLCK in the metastasis of gastric cancer in vitro and in vivo by downregualting of MLCK expression in CAF with RNAi or specific inhibitor; Aim 3: To study the mechanism of MLCK in the metastasis of gastric cancer by analyzing the differential expression of molecules in CAF with or without MLCK knockdown; Aim 4: To explore the molecular mechanism of MLCK regulation in CAF by tumor microenvironment in gastric cancer. Thus, our study identified the critical role of CAF-MLCK in cancer-associated inflammation, EMT of gastric cancer cells and active phenotype of CAF, which all favored the metastasis of gastric cancer, at various levels from gene expression, protein regulation to system biology. These findings should thereby ultimately contribute to the development of novel CAF-targeting therapies for the metastasis of gastric cancer.