PMID- 27529686 OWN - NLM STAT- MEDLINE DCOM- 20170512 LR - 20220408 IS - 1097-0215 (Electronic) IS - 0020-7136 (Linking) VI - 139 IP - 11 DP - 2016 Dec 1 TI - Voltage-gated sodium channel Nav 1.7 promotes gastric cancer progression through MACC1-mediated upregulation of NHE1. PG - 2553-69 LID - 10.1002/ijc.30381 [doi] AB - 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-kappaB 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. CI - (c) 2016 UICC. FAU - Xia, Jianling AU - Xia J AD - Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. FAU - Huang, Na AU - Huang N AD - Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. FAU - Huang, Hongxiang AU - Huang H AD - Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. FAU - Sun, Li AU - Sun L AD - Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. FAU - Dong, Shaoting AU - Dong S AD - Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. FAU - Su, Jinyu AU - Su J AD - Department of Pathophysiology, Key Lab for Shock and Microcirculation Research, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China. FAU - Zhang, Jingwen AU - Zhang J AD - Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. FAU - Wang, Lin AU - Wang L AD - Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. FAU - Lin, Li AU - Lin L AD - Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. FAU - Shi, Min AU - Shi M AD - Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. FAU - Bin, Jianping AU - Bin J AD - Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. FAU - Liao, Yulin AU - Liao Y AD - Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. FAU - Li, Nailin AU - Li N AD - Karolinska Institute, Department of Medicine-Solna, Clinical Pharmacology Group, Karolinska University Hospital-Solna, Stockholm, 17176, Sweden. FAU - Liao, Wangjun AU - Liao W AD - Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. nfyyliaowj@163.com. LA - eng PT - Journal Article DEP - 20160826 PL - United States TA - Int J Cancer JT - International journal of cancer JID - 0042124 RN - 0 (Cation Transport Proteins) RN - 0 (HGF protein, human) RN - 0 (MACC1 protein, human) RN - 0 (NAV1.7 Voltage-Gated Sodium Channel) RN - 0 (NF-kappa B) RN - 0 (Proto-Oncogene Proteins c-jun) RN - 0 (SCN9A protein, human) RN - 0 (SLC9A1 protein, human) RN - 0 (Sodium-Hydrogen Exchanger 1) RN - 0 (Sodium-Hydrogen Exchangers) RN - 0 (Trans-Activators) RN - 0 (Transcription Factors) RN - 67256-21-7 (Hepatocyte Growth Factor) RN - EC 2.7.10.1 (Proto-Oncogene Proteins c-met) SB - IM MH - Animals MH - Cation Transport Proteins/biosynthesis/genetics/*metabolism MH - Cell Line, Tumor MH - Disease Progression MH - Female MH - Gene Knockdown Techniques MH - Hepatocyte Growth Factor/metabolism MH - Heterografts MH - Humans MH - MAP Kinase Signaling System MH - Mice MH - Mice, Nude MH - NAV1.7 Voltage-Gated Sodium Channel/biosynthesis/genetics/*metabolism MH - NF-kappa B/metabolism MH - Neoplasm Invasiveness MH - Proto-Oncogene Proteins c-jun/metabolism MH - Proto-Oncogene Proteins c-met/metabolism MH - Sodium-Hydrogen Exchanger 1 MH - Sodium-Hydrogen Exchangers/biosynthesis/genetics/*metabolism MH - Stomach Neoplasms/genetics/*metabolism/pathology MH - Trans-Activators MH - Transcription Factors/*metabolism MH - Up-Regulation OTO - NOTNLM OT - Gastric cancer OT - MACC1 OT - NHE1 OT - Nav1.7 OT - Tumor progression EDAT- 2016/08/17 06:00 MHDA- 2017/05/13 06:00 CRDT- 2016/08/17 06:00 PHST- 2016/01/20 00:00 [received] PHST- 2016/07/19 00:00 [revised] PHST- 2016/07/26 00:00 [accepted] PHST- 2016/08/17 06:00 [entrez] PHST- 2016/08/17 06:00 [pubmed] PHST- 2017/05/13 06:00 [medline] AID - 10.1002/ijc.30381 [doi] PST - ppublish SO - Int J Cancer. 2016 Dec 1;139(11):2553-69. doi: 10.1002/ijc.30381. Epub 2016 Aug 26.