TMPRSS4 induces invasion and proliferation of prostate cancer cells through induction of Slug and cyclin D1
Metrics: PDF 1838 views | HTML 2600 views | ?
Yunhee Lee1,2, Dongjoon Ko2,3, Hye-Jin Min2, Sol Bi Kim2,3, Hye-Mi Ahn2, Younghoon Lee1, Semi Kim2,1,3
1Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejon 34141, Korea
2Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon 34141, Korea
3Department of Functional Genomics, Korea University of Science and Technology, Daejon 34113, Korea
Semi Kim, email: [email protected]
Keywords: TMPRSS4, prostate cancer, invasion, proliferation, Slug
Received: July 29, 2015 Accepted: June 17, 2016 Published: July 2, 2016
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.