title: TMPRSS4 promotes invasiveness of human gastric cancer cells through activation of NF-κB/MMP-9 signaling.
abstract: Transmembrane protease serine 4 (TMPRSS4) is a type-II transmembrane serine protease that is frequently upregulated in human cancers. However, little is known about the biological roles of TMPRSS4 in gastric cancer. In this study, we examined the effect of TMPRSS4 on gastric cancer cell proliferation, migration, and invasion. The expression and secretion of matrix metalloproteinase-9 (MMP-9) and activation of nuclear factor-κB (NF-κB) were determined. The involvement of NF-κB/MMP-9 signaling was checked. Our data showed that TMPRSS4 silencing significantly (P<0.05) reduced the migration and invasion of AGS and MKN-45 gastric cancer cells, without affecting cell proliferation. Overexpression of TMPRSS4 significantly promoted cell migration and invasion. The expression and secretion of MMP-9 was significantly (P<0.05) enhanced in TMPRSS4-overexpressing cells. TMPRSS4-overexpressing cells had a significantly (P<0.05) lower level of IκBα and higher level of nuclear NF-κB. Luciferase reporter assay confirmed that overexpression of TMPRSS4 resulted in a 3-5-fold increase in NF-κB-dependent luciferase activity. Downregulation of MMP-9 significantly (P<0.05) reversed the invasiveness of gastric cancer cells induced by TMPRSS4 overexpression. Moreover, pharmacological inhibition of NF-κB attenuated the invasion of TMPRSS4-overexpressing cells and the expression of MMP-9. Upregulation of TMPRSS4 enhances the invasiveness of gastric cancer cells, largely through activation of NF-κB and induction of MMP-9 expression. Our study provides the rationale for targeting TMPRSS4 in the treatment of gastric cancer.
authors.affiliation: Department of Digestive Diseases, Wenzhou Central Hospital, Wenzhou, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Jin
authors.affiliation: Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
authors.forename: Xian
authors.initials: X
authors.lastname: Shen
authors.affiliation: Department of Surgery, Wenzhou Central Hospital, Wenzhou, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Digestive Diseases, Wenzhou Central Hospital, Wenzhou, China.
authors.forename: Luo-wen
authors.initials: LW
authors.lastname: Bao
authors.affiliation: Department of Digestive Diseases, Wenzhou Central Hospital, Wenzhou, China. Electronic address: lim_zhu_2015@163.com.
authors.forename: Li-ming
authors.initials: LM
authors.lastname: Zhu
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D016328:NF-kappa B / Q000096:biosynthesis*; D009361:Neoplasm Invasiveness; D010957:Plasmids / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D011817:Rabbits; D012697:Serine Endopeptidases / Q000235:genetics*; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D014162:Transfection / Q000379:methods; D015854:Up-Regulation
chemical_list: D008565:Membrane Proteins; D016328:NF-kappa B; D034741:RNA, Small Interfering; D012697:Serine Endopeptidases; C528837:TMPRSS4 protein, human; D020780:Matrix Metalloproteinase 9
keywords: Aggressiveness; Gastric cancer; NF-κB signaling; TMPRSS4; Therapeutic target