title: Voltage-gated sodium channel Nav 1.7 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.
authors.affiliation: Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
authors.forename: Jianling
authors.initials: J
authors.lastname: Xia
authors.affiliation: Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
authors.forename: Na
authors.initials: N
authors.lastname: Huang
authors.affiliation: Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
authors.forename: Hongxiang
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
authors.forename: Li
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
authors.forename: Shaoting
authors.initials: S
authors.lastname: Dong
authors.affiliation: Department of Pathophysiology, Key Lab for Shock and Microcirculation Research, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.
authors.forename: Jinyu
authors.initials: J
authors.lastname: Su
authors.affiliation: Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
authors.forename: Jingwen
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.affiliation: Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
authors.forename: Min
authors.initials: M
authors.lastname: Shi
authors.affiliation: Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Bin
authors.affiliation: Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
authors.forename: Yulin
authors.initials: Y
authors.lastname: Liao
authors.affiliation: Karolinska Institute, Department of Medicine-Solna, Clinical Pharmacology Group, Karolinska University Hospital-Solna, Stockholm, 17176, Sweden.
authors.forename: Nailin
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. nfyyliaowj@163.com.
authors.forename: Wangjun
authors.initials: W
authors.lastname: Liao
mesh_terms: D000818:Animals; D027682:Cation Transport Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D055785:Gene Knockdown Techniques; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D008819:Mice, Nude; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015534:Trans-Activators; D014157:Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D027682:Cation Transport Proteins; C066855:HGF protein, human; C544162:MACC1 protein, human; D062556:NAV1.7 Voltage-Gated Sodium Channel; D016328:NF-kappa B; D016755:Proto-Oncogene Proteins c-jun; C486866:SCN9A protein, human; C490998:SLC9A1 protein, human; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D015534:Trans-Activators; D014157:Transcription Factors; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met
keywords: Gastric cancer; MACC1; NHE1; Nav1.7; Tumor progression