电压门控钠离子通道Nav1.7通过MACC1调控NHE1促进胃癌增殖的机制研究

项目名称： 电压门控钠离子通道Nav1.7通过MACC1调控NHE1促进胃癌增殖的机制研究

项目编号： No.81502116

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 孙丽

作者单位： 南方医科大学

项目金额： 18万元

中文摘要： 电压门控钠离子通道（VGSCs）可促进肿瘤生长。我们的预实验显示：VGSCs中的一员Nav1.7在胃癌中高表达，抑制Nav1.7活性可下调结肠癌转移相关基因-1 （MACC1）及Na+/H+交换泵-1（NHE1）表达，敲低MACC1可抑制NHE1表达。但Nav1.7在胃癌中具体作用及机制尚不明确。已知VGSCs可调控p38/NF-κB信号轴，同时生物学信息预测：NF-κB能与MACC1启动子结合；MACC1可调控HGF/c-MET信号通路，且其下游分子c-Jun参与调控多种基因。因此，我们假设：①Nav1.7上调NHE1表达，促进胃癌增殖；②Nav1.7通过p38/NF-κB信号轴调控MACC1；③MACC1通过HGF/c-MET-c-Jun信号轴上调NHE1。本课题拟探讨Nav1.7在胃癌中的作用，明确“Nav1.7-MACC1-NHE1”与胃癌增殖的关系，为胃癌防治提供实验依据。

中文关键词： 胃肿瘤；电压门控钠离子通道；结肠癌转移相关基因-1；Na+/H+交换泵-1；增殖

英文摘要： Voltage-gated sodium channels (VGSCs) could promote tumor proliferation. Our preliminary experiments showed that Nav1.7, a member of VGSCs, was highly expressed in gastric cancer(GC) tissues than in the adjacent normal tissues; inhibition of Nav1.7 activity downregulated the expression of metastasis-associated in colon cancer-1(MACC1) and Na+/H+ exchanger type 1(NHE1); besides, MACC1 knockdown decreased the expression of NHE1. However, the function of Nav1.7 and the detailed mechanism remain unknown. It is reported that VGSCs modulate the p38 /NF-κB signal axis. Meanwhile, our bioinformatic prediction showed that NF-κB could bind to the MACC1 promoter region. Moreover, MACC1 modulates HGF/c-MET signal axis and its downstream molecular c-Jun is involved in the regulation of numerous genes. Therefore, we got the following hypothesis: ①Nav1.7 promotes GC proliferation through upregulating NHE1 expression; ②Nav1.7 regulates expression of MACC1 through the p38/NF-κB signal axis; ③MACC1 upregulates NHE1 through the HGF/c-Met-c-Jun signal axis. The present study intends to explore the role of Nav1.7 in GC and identify the potential relationship between Nav1.7-MACC1-NHE1 and GC proliferation, thus providing the experimental evidence for the prevention and treatment of GC.

英文关键词： gastric cancer;Voltage-gated sodium channels ;Metastasis-associated in colon cancer-1;Na+/H+ transporter gene-1;proliferation