TMPRSS4 induces invasion and proliferation of prostate cancer cells through induction of Slug and cyclin D1.
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.
['Lee|Yunhee|Y|', 'Ko|Dongjoon|D|', 'Min|Hye-Jin|HJ|', 'Kim|Sol Bi|SB|', 'Ahn|Hye-Mi|HM|', 'Lee|Younghoon|Y|', 'Kim|Semi|S|']
D000818:Animals D045744:Cell Line, Tumor D049109:Cell Proliferation D019938:Cyclin D1 D018450:Disease Progression D058750:Epithelial-Mesenchymal Transition D015972:Gene Expression Regulation, Neoplastic D006801:Humans D008297:Male D008565:Membrane Proteins D051379:Mice D008807:Mice, Inbred BALB C D008819:Mice, Nude D009361:Neoplasm Invasiveness D009362:Neoplasm Metastasis D009368:Neoplasm Transplantation D011471:Prostatic Neoplasms D034741:RNA, Small Interfering D012697:Serine Endopeptidases D012878:Skin Neoplasms D000071250:Snail Family Transcription Factors D015854:Up-Regulation
TMPRSS4 invasion proliferation prostate cancer Slug