Voltage-gated sodium channel Nav 1.7 promotes gastric cancer progression through MACC1-mediated upregulation of NHE1
Voltage-gated sodium channel Nav 1.7 promotes gastric cancer progression through MACC1-mediated upregulation of NHE1
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电压门控钠通道 Nav 1.7 通过 MACC1 介导的 NHE1 上调促进胃癌进展
DOI：
10.1002/ijc.30381
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发表时间：
2016
影响因子：
6.4
通讯作者：
Liao Wangjun
中科院分区：
文献类型：
--
作者：
Xia Jianling;Huang Na;Huang Hongxiang;Sun Li;Dong Shaoting;Su Jinyu;Zhang Jingwen;Wang Lin;Lin Li;Shi Min;Bin Jianping;Liao Yulin;Li Nailin;Liao Wangjun
电压门控钠通道（VGSC）在几种人类癌症中异常表达，影响癌细胞行为;然而，它们在胃癌（GC）中的作用以及这些通道与致瘤信号之间的联系仍不清楚。本研究的目的是确定VGSC Nav1.7在胃癌进展中的临床病理学意义和作用，并研究相关机制。在此，我们报告了编码Nav 1. 7的SCN 9 A基因是胃癌组织样本和两种胃癌细胞系（BGC-823和MKN-28细胞）中表达最丰富的VGSC亚型，通过真实的-time PCR也经常发现SCN 9 A在胃癌组织中的表达水平高于非恶性组织。在通过免疫组织化学评估的319份GC标本中，Nav1.7表达与预后相关，转运蛋白Na+/H+交换器-1（NHE 1）和结肠癌转移相关癌蛋白-1（MACC 1）表达与预后相关。Nav1.7抑制导致电压门控钠电流降低，NHE 1表达降低，细胞外pH升高和细胞内pH降低，最终降低GC细胞的侵袭和增殖率以及裸鼠中GC异种移植物的生长。Nav1.7抑制导致MACC 1表达减少，而MACC 1抑制导致体外和体内NHE 1表达减少。从机制上讲，抑制Nav1.7通过ap 38激活减少NF-κB p65核转位，从而减少MACC 1表达。MACC 1的下调降低了c-Jun磷酸化，随后降低了NHE 1的表达，而加入肝细胞生长因子（HGF），一种c-Met生理配体，逆转了这种作用。这些结果表明，Nav1.7通过MACC 1介导的NHE 1上调促进GC进展。因此，Nav1.7是GC的潜在预后标志物和/或治疗靶点。
Voltage‐gated sodium channels (VGSCs), which are aberrantly expressed in several human cancers, affect cancer cell behavior; however, their role in gastric cancer (GC) and the link between these channels and tumorigenic signaling remain unclear. The aims of this study were to determine the clinicopathological significance and role of the VGSC Nav1.7 in GC progression and to investigate the associated mechanisms. Here, we report that theSCN9Agene encoding Nav1.7 was the most abundantly expressed VGSC subtype in GC tissue samples and two GC cell lines (BGC‐823 and MKN‐28 cells).SCN9Aexpression levels were also frequently found to be elevated in GC samples compared to nonmalignant tissues by real‐time PCR. In the 319 GC specimens evaluated by immunohistochemistry, Nav1.7 expression was correlated with prognosis, and transporter Na+/H+exchanger‐1 (NHE1) and oncoprotein metastasis‐associated in colon cancer‐1 (MACC1) expression. Nav1.7 suppression resulted in reduced voltage‐gated sodium currents, decreased NHE1 expression, increased extracellular pH and decreased intracellular pH, and ultimately, reduced invasion and proliferation rates of GC cells and growth of GC xenografts in nude mice. Nav1.7 inhibition led to reduced MACC1 expression, while MACC1 inhibition resulted in reduced NHE1 expressionin vitroandin vivo. Mechanistically, the suppression of Nav1.7 decreased NF‐κB p65 nuclear translocationviap38 activation, thus reducing MACC1 expression. Downregulation of MACC1 decreased c‐Jun phosphorylation and subsequently reduced NHE1 expression, whereas the addition of hepatocyte growth factor (HGF), a c‐Met physiological ligand, reversed the effect. These results indicate that Nav1.7 promotes GC progression through MACC1‐mediated upregulation of NHE1. Therefore, Nav1.7 is a potential prognostic marker and/or therapeutic target for GC.