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

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.

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。

研究背景：已知电压门控钠通道(VGSCs)在多种肿瘤组织中异常表达，一定程度上影响肿瘤的恶性生物学行为。然而，它们在胃癌(GC)中的作用以及这些通道与肿瘤发生信号之间的联系尚不清楚。.研究主要内容：本研究拟探究电压门控钠离子通道Nav1.7在胃癌进展中的临床病理意义和作用，并探究其可能的内在机制。.研究结果及关键数据：在本研究中，我们发现胃癌组织及胃癌细胞中存在VGSCs，其中Nav1.7（gene：SCN9A）是表达量最高的VGSCs亚型，在胃癌组织中显著高表达，与胃癌不良预后相关。进一步的分析显示，Nav1.7的表达与转运蛋白Na1/H1交换蛋白1 (NHE1)表达正相关（r=50.496, p<0.001）。提示Nav1.7通过调控NHE1促进胃癌进展。随后我们在体内外实验进行验证。结果显示抑制VGSCs活性，可显著降低NHE1表达，降低细胞内pH降低，引起胃癌细胞侵袭和增殖率降低，裸鼠移植瘤生长抑制。机制上我们发现，抑制Nav1.7可显著下调MACC1表达，而抑制MACC1可导致NHE1的表达受抑。进一步的我们发现，Nav1.7通过抑制p38激活从而诱导NF-κB p65核转位，促进MACC1的表达。同时，MACC1可诱导c-Jun的磷酸化，促进NHE1的表达，而c-Met抑制剂的加入则可逆转上述现象。.研究结论：Nav1.7通过MACC1介导NHE1的上调促进胃癌进展。.科学意义：通过本研究，阐明电压门控钠离子通道Nav1.7在促进胃癌进展中的作用，明确“Nav1.7-MACC1-NHE1”与胃癌增殖的关系，探讨离子通道病变在胃癌发生发展中的作用，为胃癌防治提供新的思路和实验依据。