MGr1-Ag/FAK/Twist信号通路在胃癌嗜神经浸润的作用机制研究

Perineural invasion is defined as tumor cells within any layers of the nerve sheath or tumor in close proximity to nerve and involving at least one third of its circumference, and is a new way of gastric cancer metastasis. Our previous work discovered that MGr1-Ag, a cell adhesion molecule, plays a key role in multi-drug resistance of gastric cancer. Successive work identified MGr1-Ag had contributed to various malignant phenotypes including tumor invasion, metastasis. In our previous work, we found that expression of MGr1-Ag was associated with perineural invasion of gastric cancer. The activation of MGr1-Ag was interacted with FAK and activated MEK/ERK downstream, and then regulated the function and expression of Twist. High-throughput screening showed Twist was downstream molecule of MGr1-Ag again. Twist played critical roles in the perineural invasion as reported in the literature. These results imply that MGr1-Ag and FAK may play key roles in perineural invasion, and may participated in this process as a form of FAK/Twist pathway. Based on our previous work, we plan to study the role of MGr1-Ag and FAK in perineural invasion, and uncover the effect of MGr1-Ag/FAK/Twist pathway in perineural invasion. We hope that the current project will provide novel insights in underlying mechanisms of perineural invasion in gastric cancer.

嗜神经浸润指肿瘤细胞穿透神经外膜进入神经束内或包绕神经外膜1/3以上进行转移，是胃癌转移的新途径。MGr1-Ag是我实验室发现并证实与胃癌耐药相关粘附分子，后经研究证实该分子在胃癌侵袭、转移等多种恶性表型中发挥重要作用。我们前期研究发现，MGr1-Ag表达与胃癌嗜神经浸润密切相关；MGr1-Ag通过与FAK相互作用激活MEK/ERK通路，进而调控下游分子Twist的功能及表达；高通量筛选再次证实Twist是MGr1-Ag的下游分子；文献表明Twist是嗜神经浸润关键分子。以上结果提示：MGr1-Ag可能通过FAK/Twist通路在胃癌嗜神经浸润中发挥作用。本项目拟在前期研究基础上，研究MGr1-Ag和FAK在嗜神经浸润中的作用，揭示MGr1-Ag/FAK/Twist通路在嗜神经浸润中的作用及分子机制，为深入理解胃癌嗜神经浸润的发生机制提供新的实验室证据。

嗜神经浸润指肿瘤细胞穿透神经外膜进入神经束内或至少包绕1/3神经外膜进行转移，是胃癌转移新途径。MGr1-Ag是我实验室发现并证实与胃癌耐药相关粘附分子，后经研究证实该分子在胃癌转移、侵袭等多种恶性表型中发挥重要作用。我们前期研究发现，MGr1-Ag表达与嗜神经浸润密切相关，为研究其在嗜神经浸润中发挥的作用，我们进行了进一步研究。首先，我们通过免疫组织化学染色证实胃癌组织中存在嗜神经浸润的现象，统计分析发现是影响患者预后的独立危险因素，与MGr1-Ag的表达密切相关；通过体内外实验证实，胃癌细胞可以发生嗜神经浸润。其次，利用Western-blot和PCR实验证实，MGr1-Ag在胃癌组织及细胞中高表达，且与嗜神经浸润显著相关；进一步通过Transwell和嗜神经浸润体外共培养发现，MGr1-Ag高表达增强胃癌侵袭转移，促进嗜神经浸润抑制MGr1-Ag的表达水平，胃癌的转移和嗜神经浸润水平下降。最后，分子生物学实验发现，MGr1-Ag与LN识别后，可以诱导细胞内FAK的磷酸化，MGr1-Ag与LN识别后，通过诱导FAK的磷酸化激活ERK1/2通路，进而调控下游效应分子twist1的表达水平，促进胃癌转移和嗜神经浸润。本项目在前期研究基础上，研究MGr1-Ag和FAK在嗜神经浸润中的作用，揭示MGr1-Ag/FAK/Twist通路在嗜神经浸润中的作用及分子机制，为深入理解胃癌嗜神经浸润的发生机制提供新的实验室证据。