title: TMPRSS4 induces invasion and proliferation of prostate cancer cells through induction of Slug and cyclin D1.
abstract: TMPRSS4 is a novel type II transmembrane serine protease found at the cell surface that is highly expressed in pancreatic, colon, and other cancer tissues. Previously, we demonstrated that TMPRSS4 mediates tumor cell invasion, migration, and metastasis. We also found that TMPRSS4 activates the transcription factor activating protein-1 (AP-1) to induce cancer cell invasion. Here, we explored TMPRSS4-mediated cellular functions and the underlying mechanisms. TMPRSS4 induced Slug, an epithelial-mesenchymal transition (EMT)-inducing transcription factor, and cyclin D1 through activation of AP-1, composed of c-Jun and activating transcription factor (ATF)-2, which resulted in enhanced invasion and proliferation of PC3 prostate cancer cells. In PC3 cells, not only c-Jun but also Slug was required for TMPRSS4-mediated proliferation and invasion. Interestingly, Slug induced phosphorylation of c-Jun and ATF-2 to activate AP-1 through upregulation of Axl, establishing a positive feedback loop between Slug and AP-1, and thus induced cyclin D1, leading to enhanced proliferation. Using data from The Cancer Genome Atlas, we found that Slug expression positively correlated with that of c-Jun and cyclin D1 in human prostate cancers. Expression of Slug was positively correlated with that of cyclin D1 in various cancer cell lines, whereas expression of other EMT-inducing transcription factors was not. This study demonstrates that TMPRSS4 modulates both invasion and proliferation via Slug and cyclin D1, which is a previously unrecognized pathway that may regulate metastasis and cancer progression.
authors.affiliation: Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejon 34141, Korea.|Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon 34141, Korea.
authors.forename: Yunhee
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon 34141, Korea.|Department of Functional Genomics, Korea University of Science and Technology, Daejon 34113, Korea.
authors.forename: Dongjoon
authors.initials: D
authors.lastname: Ko
authors.affiliation: Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon 34141, Korea.
authors.forename: Hye-Jin
authors.initials: HJ
authors.lastname: Min
authors.affiliation: Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon 34141, Korea.|Department of Functional Genomics, Korea University of Science and Technology, Daejon 34113, Korea.
authors.forename: Sol Bi
authors.initials: SB
authors.lastname: Kim
authors.affiliation: Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon 34141, Korea.
authors.forename: Hye-Mi
authors.initials: HM
authors.lastname: Ahn
authors.affiliation: Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejon 34141, Korea.
authors.forename: Younghoon
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon 34141, Korea.|Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejon 34141, Korea.|Department of Functional Genomics, Korea University of Science and Technology, Daejon 34113, Korea.
authors.forename: Semi
authors.initials: S
authors.lastname: Kim
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism*; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism*; D012878:Skin Neoplasms / Q000378:metabolism; D000071250:Snail Family Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C530104:CCND1 protein, human; D008565:Membrane Proteins; D034741:RNA, Small Interfering; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D019938:Cyclin D1; D012697:Serine Endopeptidases; C528837:TMPRSS4 protein, human
keywords: Slug; TMPRSS4; invasion; proliferation; prostate cancer