CEACAM6表达调控及其通过Integrinα5β1促进胃癌侵袭转移的分子机制研究

Tumor metastasis is the main cause of death of gastric cancer patients. Our previous study showed that CEACAM6 was significantly increased in gastric cancer and promoted gastric cancer metastasis via activating AKT、FAK signaling pathway. However, the molecular mechanism of CEACAM6 high expressed in gastric cancer and how it initiates cell signal transduction remain unclear. NF-κB plays an important role in the tumorigenesis and development of gastric cancer. It is predicted that NF-κB may bind with the promoter of CEACAM6. Down-regulation of MLL1 expression can inhibit the expression of CEACAM6. NF-κB can interact with MLL1 in gastric cancer. Moreover, CEACAM6 and Integrinα5 can interact with each other and co-locate on the surface of gastric cancer cell membrane. Therefore, we propose the following scientific hypothesis: 1. NF-κB recruits MLL1 to bind the promoter of CEACAM6 and then promoting its expression; 2. CEACAM6 regulates the activity of AKT、FAK pathway depending on Integrinα5β1, in turn promoting gastric cancer invasion and metastasis. The confirmation of these hypothesis will reveal CEACAM6 expression regulating mechanism and the molecular mechanism of CEACAM6 promoting tumor invasion and metastasis in gastric cancer. This study will provide basis foundation of research, which supports CEACAM6 serving as a tumor marker and gastric cancer therapeutic target for clinical application.

肿瘤转移是造成胃癌患者死亡的主要原因，我们前期研究发现CEACAM6在胃癌中表达显著升高，可以激活AKT、FAK通路促进胃癌转移。但CEACAM6在胃癌中表达升高及其传递细胞信号的分子机制尚不清楚。NF-κB在胃癌发生发展中具有重要的作用，可以与CEACAM6的启动子结合；下调MLL1可以抑制CEACAM6的表达，NF-κB与MLL1存在相互作用。另外，CEACAM6与Integrinα5相互作用并共定位在胃癌细胞膜表面。由此我们提出如下科学假说：1.NF-κB与CEACAM6启动子结合，招募MLL1，促进其表达；2.CEACAM6依赖于Integrinα5β1传递细胞信号，激活AKT、FAK通路，促进胃癌侵袭转移。对这些假说的验证，将揭示CEACAM6的表达调控及其促进胃癌侵袭转移的分子机制，为以CEACAM6为肿瘤标志物和治疗靶点的临床应用提供研究基础。

癌胚抗原相关细胞黏附分子 6（Carcinoembryonic antigen-related cell adhesion molecule 6, CEACAM6）在胃癌组织中的表达显著升高，在胃癌细胞中过表达CEACAM6可以通过激活AKT/FAK信号通路促进细胞增殖和转移，而抑制CEACAM6的表达可以显著降低胃癌细胞的增殖和转移。在本项目中，我们研究在胃癌中CEACAM6的表达调控机制及其促进胃癌侵袭转移的分子机制。结果表明，CEACAM6与Integrinα5相互作用，共定位在胃癌细胞膜表面，抑制Integrinα5的表达可以通过抑制AKT/FAK信号通路而降低CEACAM6促进胃癌胞增殖和转移的能力。在高表达CEACAM6的胃癌细胞中沉默Integrinα5的表达，可以抑制小鼠移植瘤的生长和肺转移。另外，CHIP实验结果表明NF-KB可以与CEACAM6的启动子区域结合，激活NF-KB可以促进CEACAM6的表达。组蛋白甲基化转移酶MLL1沉默可以抑制CEACAM6的表达，激活NF-KB后促进p65入核，入核的p65与MLL1相互结合，进而激活CEACAM6启动子，促进其表达。本研究揭示了NF-KB/ MLL1调控CEACAM6表达的分子机制和通过Integrinα5/AKT/FAK信号通路调控胃癌侵袭转移的下游分子机制，为CEACAM6作为胃癌肿瘤标志物和治疗靶点奠定了研究基础。