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Voltage‐gated sodium channel Na v 1.7 promotes gastric cancer progression through MACC1‐mediated upregulation of NHE1
Author(s) -
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
Publication year - 2016
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.30381
Subject(s) - downregulation and upregulation , sodium channel , sodium , cancer , chemistry , voltage , cancer research , medicine , physics , biochemistry , gene , organic chemistry , quantum mechanics
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 Na v 1.7 in GC progression and to investigate the associated mechanisms. Here, we report that the SCN9A gene encoding Na v 1.7 was the most abundantly expressed VGSC subtype in GC tissue samples and two GC cell lines (BGC‐823 and MKN‐28 cells). SCN9A expression 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, Na v 1.7 expression was correlated with prognosis, and transporter Na + /H + exchanger‐1 (NHE1) and oncoprotein metastasis‐associated in colon cancer‐1 (MACC1) expression. Na v 1.7 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. Na v 1.7 inhibition led to reduced MACC1 expression, while MACC1 inhibition resulted in reduced NHE1 expression in vitro and in vivo . Mechanistically, the suppression of Na v 1.7 decreased NF‐κB p65 nuclear translocation via p38 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 Na v 1.7 promotes GC progression through MACC1‐mediated upregulation of NHE1. Therefore, Na v 1.7 is a potential prognostic marker and/or therapeutic target for GC.