Voltage-Gated Sodium Channel Na(V)1.7 Promotes Gastric Cancer Progression Through Macc1-Mediated Upregulation Of Nhe1

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-B 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.What's new? Several human cancers have been shown to express abnormal levels of voltage-gated sodium channels (VGSCs). However, the role of these membrane ion channels in gastric cancer (GC) remains unclear. In this study, the authors found that overexpression of VGSC-Na(v)1.7 indicated a poor prognosis for GC patients. It was also correlated with upregulation of NHE1 and MACC1, and overexpression of that pathway increased proliferation of GC cells in mice. VGSC-Na(v)1.7 may thus be a useful prognostic marker in GC, as well as a potential therapeutic target.