title: Na+/H+ exchanger 1, Na+/Ca2+ exchanger 1 and calmodulin complex regulates interleukin 6-mediated cellular behavior of human hepatocellular carcinoma.
abstract: Interleukin 6 (IL6) is a key cytokine involved in the development and progression of inflammation-associated hepatocellular carcinoma (HCC). However, the mechanisms of IL6 action on HCC remain largely unknown. Proton and Ca(2+) are two intracellular messenger ions, which are believed to play a central role in tumorigenesis and tumor progression. In this study, we found that IL6 stimulation markedly increased intracellualr pH recovery rates of human HCC cells, Huh7 and HepG2, after NH4Cl acidification, and the NH4Cl acidification induced transient intracellular Ca(2+) increases in the HCC cells. The inhibition of Na(+)/H(+) exchanger 1 (NHE1), Na(+)/Ca(2+) exchanger 1 (NCX1) and calmodulin (CaM) inhibited the IL6 stimulation-induced intracellular pH recovery increases and NH4Cl acidification-induced intracellular Ca(2+) increases. IL6 stimulation also induced the structural interaction of NHE1, NCX1 and CaM proteins. The protein expression levels of NHE1, NCX1 and CaM in native human HCC tissues were markedly higher than those in normal liver tissues. IL6 upregulated the expressions of NHE1, NCX1 and CaM in Huh7 and HepG2 cells. NHE1, NCX1 and CaM mediated the promotion of IL6 on the proliferation, migration and invasion of Huh7 and HepG2 cells and the growth of HCC in nude mice. In conclusion, IL6 activates the functional activity of NHE1 and induces the functional and structural interaction of NHE1, NCX1 and CaM. The interaction of NHE1, NCX1 and CaM mediates the effects of IL6 on human HCC.
authors.affiliation: Department of Gastroenterology, Affiliated Hospital, Zunyi Medical College, 149 Dalian Road, Zunyi 563003, China.|Digestive Disease Institute of Guizhou Province, Zunyi 563003, China.|Research Center of Medicine and Biology, Zunyi Medical College, Zunyi 563003, China.
authors.forename: Jingyu
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Gastroenterology, Affiliated Hospital, Zunyi Medical College, 149 Dalian Road, Zunyi 563003, China.|Digestive Disease Institute of Guizhou Province, Zunyi 563003, China.
authors.forename: Bei
authors.initials: B
authors.lastname: Ji
authors.affiliation: Department of Gastroenterology, Affiliated Hospital, Zunyi Medical College, 149 Dalian Road, Zunyi 563003, China.|Digestive Disease Institute of Guizhou Province, Zunyi 563003, China.|Research Center of Medicine and Biology, Zunyi Medical College, Zunyi 563003, China.
authors.forename: Guorong
authors.initials: G
authors.lastname: Wen
authors.affiliation: Department of Gastroenterology, Affiliated Hospital, Zunyi Medical College, 149 Dalian Road, Zunyi 563003, China.|Digestive Disease Institute of Guizhou Province, Zunyi 563003, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Gastroenterology, Affiliated Hospital, Zunyi Medical College, 149 Dalian Road, Zunyi 563003, China.|Digestive Disease Institute of Guizhou Province, Zunyi 563003, China.|Research Center of Medicine and Biology, Zunyi Medical College, Zunyi 563003, China.
authors.forename: Hai
authors.initials: H
authors.lastname: Jin
authors.affiliation: Department of Gastroenterology, Affiliated Hospital, Zunyi Medical College, 149 Dalian Road, Zunyi 563003, China.|Digestive Disease Institute of Guizhou Province, Zunyi 563003, China.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology, Affiliated Hospital, Zunyi Medical College, 149 Dalian Road, Zunyi 563003, China.|Digestive Disease Institute of Guizhou Province, Zunyi 563003, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Xie
authors.affiliation: Key Laboratory of Combined Multi-organ Transplantation, Zhejiang University, Hangzhou 310003, China and.|Collaborative innovation center for Diagnosis treatment of infectious diseases, Zhejiang Province, Hangzhou 310003, China.
authors.forename: Wenfeng
authors.initials: W
authors.lastname: Song
authors.affiliation: Key Laboratory of Combined Multi-organ Transplantation, Zhejiang University, Hangzhou 310003, China and.|Collaborative innovation center for Diagnosis treatment of infectious diseases, Zhejiang Province, Hangzhou 310003, China.
authors.forename: Penghong
authors.initials: P
authors.lastname: Song
authors.affiliation: Department of Gastroenterology, Affiliated Hospital, Zunyi Medical College, 149 Dalian Road, Zunyi 563003, China.|Digestive Disease Institute of Guizhou Province, Zunyi 563003, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Dong
authors.affiliation: Department of Gastroenterology, Affiliated Hospital, Zunyi Medical College, 149 Dalian Road, Zunyi 563003, China.|Digestive Disease Institute of Guizhou Province, Zunyi 563003, China.|Research Center of Medicine and Biology, Zunyi Medical College, Zunyi 563003, China.
authors.forename: Biguang
authors.initials: B
authors.lastname: Tuo
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002147:Calmodulin / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D027682:Cation Transport Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D015850:Interleukin-6 / Q000378:metabolism*; D008113:Liver Neoplasms / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D019831:Sodium-Calcium Exchanger / Q000378:metabolism*; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*
chemical_list: D002147:Calmodulin; D027682:Cation Transport Proteins; C508600:IL6 protein, human; D015850:Interleukin-6; D034741:RNA, Small Interfering; C490998:SLC9A1 protein, human; D019831:Sodium-Calcium Exchanger; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; C110374:sodium-calcium exchanger 1