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.
Highlights
The metastatic cascade is a complex process consisting of a number of important steps that include local invasion, intravasation, circulation, extravasation, micrometastasis, and metastatic colonization [1]
We observed that c-Jun induced a 1.89fold increase in cyclin D1 promoter (−962/+134) activity (Figure 2F). These results indicate that activation of c-Jun and activating transcription factor (ATF)-2 mainly by Jun N-terminal kinase (JNK) signaling activity plays an important role in cyclin D1 and Slug expression mediated by TMPRSS4
We previously reported that TMPRSS4 induces the invasion and epithelial-mesenchymal transition (EMT) of colon cancer cells via upregulation of integrin α5 [16, 17]
Summary
The metastatic cascade is a complex process consisting of a number of important steps that include local invasion, intravasation, circulation, extravasation, micrometastasis, and metastatic colonization [1]. During EMT, epithelial cells undergo molecular changes; epithelial markers such as E-cadherin are downregulated and mesenchymal markers such as vimentin are upregulated [3]. These changes are usually mediated by EMT-inducing transcription factors directly or indirectly [5,6,7]. Tumor cells may reverse the EMT process to allow metastatic growth in distant sites/organs, the underlying mechanisms remain unclear
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