Voltage‐gated sodium channel Na_v1.7 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 remain unclear. The aims of this study were to determine the clinicopathological significance and role of the VGSC Nav 1.7 in GC progression and to investigate the associated mechanisms. Here, we report that the SCN9A gene encoding Nav 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, Nav 1.7 expression was correlated with prognosis, and transporter Na(+) /H(+) exchanger-1 (NHE1) and oncoprotein metastasis-associated in colon cancer-1 (MACC1) expression. Nav 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. Nav 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 Nav 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 Nav 1.7 promotes GC progression through MACC1-mediated upregulation of NHE1. Therefore, Nav 1.7 is a potential prognostic marker and/or therapeutic target for GC.

Hypoxia-Inducible Factors and Cancer

“…Sixth, HIF-1α increases transcription of lactate transporters, including monocarboxylate transporter 4 and NHE1 exchanger present on tumor cell membranes [68, 69] to cope with intracellular lactic acidosis [56]. Elevation of these transporters is associated with poor prognosis in lung and stomach cancer [70, 71]. HIF-1α also buffers pH by upregulating carbonic anhydrase 9 and 12, whose protein products catalyze hydration of CO 2 into bicarbonate.…”

(Patho-)Physiology of Na+/H+ Exchangers (NHEs) in the Digestive System

“…• Gastric cancer Paehler Vor der Nolte et al, 2017 Xue et al, 2011Czepán et al, 2012Liu et al, 2008He et al, 2010;Nagata et al, 2011;Hosogi et al, 2012;Xia et al, 2016;Xie et al, 2017 NHE1 Intestine…”

Ion channels or aquaporins as novel molecular targets in gastric cancer

“…The study results demonstrated that Na v 1.7 controls GC cell invasion and proliferation by MACC1-mediated upregulation of NHE1. Therapies that specifically target Na v 1.7 might successfully impede GC progression [73]. However, there have been no other reports on VGSCs in GC.…”

“…Our study showed the VGSC inhibitor tetrodotoxin (TTX) decreased MACC1 and NHE1 expressions, which decreased the extracellular pH and increased the intracellular pH. This affected the GC cell proliferation and invasion in vitro [73]. However, we did not use TTX in the experiments on mice, which should be done in the future.…”