Voltage-gated sodium channel Nav1.7 promotes gastric cancer progression through MACC1-mediated upregulation of NHE1

Abstract

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 remains unclear. The aims of this study were to determine the clinicopathological significance and role of the VGSC Na_v1.7 in GC progression and to investigate the associated mechanisms. Here, we report that the SCN9A gene encoding Na_v1.7 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_v1.7 expression was correlated with prognosis, and transporter Na⁺/H⁺ exchanger-1 (NHE1) and oncoprotein metastasis-associated in colon cancer-1 (MACC1) expression. Na_v1.7 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_v1.7 inhibition led to reduced MACC1 expression, while MACC1 inhibition resulted in reduced NHE1 expression in vitro and in vivo. Mechanistically, the suppression of Na_v1.7 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_v1.7 promotes GC progression through MACC1-mediated upregulation of NHE1. Therefore, Na_v1.7 is a potential prognostic marker and/or therapeutic target for GC. This article is protected by copyright. All rights reserved.

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