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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.

SUBMITTER: Lee Y

PROVIDER: S-EPMC5226585 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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TMPRSS4 induces invasion and proliferation of prostate cancer cells through induction of Slug and cyclin D1.

Lee Yunhee Y Ko Dongjoon D Min Hye-Jin HJ Kim Sol Bi SB Ahn Hye-Mi HM Lee Younghoon Y Kim Semi S

Oncotarget 20160801 31

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-mes ...[more]

PMID: 27385093

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Project description:BackgroundTransmembrane serine protease 4 (TMPRSS4) is a cell surface-anchored serine protease. Elevated expression of TMPRSS4 correlates with poor prognosis in colorectal cancer, gastric cancer, prostate cancer, non-small cell lung cancer, and other cancers. Previously, we demonstrated that TMPRSS4 promotes invasion and proliferation of prostate cancer cells. Here, we investigated whether TMPRSS4 confers cancer stem-like properties to prostate cancer cells and characterized the underlying mechanisms.MethodsAcquisition of cancer stem-like properties by TMPRSS4 was examined by monitoring anchorage-independent growth, tumorsphere formation, aldehyde dehydrogenase (ALDH) activation, and resistance to anoikis and drugs in vitro and in an early metastasis model in vivo. The underlying molecular mechanisms were evaluated, focusing on stemness-related factors regulated by epithelial-mesenchymal transition (EMT)-inducing transcription factors. Clinical expression and significance of TMPRSS4 and stemness-associated factors were explored by analyzing datasets from The Cancer Genome Atlas (TCGA).ResultsTMPRSS4 promoted anchorage-independent growth, ALDH activation, tumorsphere formation, and therapeutic resistance of prostate cancer cells. In addition, TMPRSS4 promoted resistance to anoikis, thereby increasing survival of circulating tumor cells and promoting early metastasis. These features were accompanied by upregulation of stemness-related factors such as SOX2, BMI1, and CD133. SLUG and TWIST1, master EMT-inducing transcription factors, made essential contributions to TMPRSS4-mediated cancer stem cell (CSC) features through upregulation of SOX2. SLUG stabilized SOX2 via preventing proteasomal degradation through its interaction with SOX2, while TWIST1 upregulated transcription of SOX2 by interacting with the proximal E-box element in the SOX2 promoter. Clinical data showed that TMPRSS4 expression correlated with the levels of SOX2, PROM1, SNAI2, and TWIST1. Expression of SOX2 was positively correlated with that of TWIST1, but not with other EMT-inducing transcription factors, in various cancer cell lines.ConclusionsTogether, these findings suggest that TMPRSS4 promotes CSC features in prostate cancer through upregulation of the SLUG- and TWIST1-induced stem cell factor SOX2 beyond EMT. Thus, TMPRSS4/SLUG-TWIST1/SOX2 axis may represent a novel mechanism involved in the control of tumor progression.

Project description:Accumulating evidence has indicated that aberrant expression of long non-coding RNAs (lncRNAs) is an important oncogenic factor. The aim of the present study was to investigate the role of LINC01296, an lncRNA that exerts a tumor?promoting function in many cancers, in the regulation of proliferation, metastasis and the cell cycle of osteosarcoma. The expression of LINC01296 in osteosarcoma tissues and adjacent healthy tissues of 30 patients was analyzed by quantitative real?time PCR (qRT?PCR). The relationship between LINC01296 expression and the survival of patients with osteosarcoma was also explored. The expression levels of LINC01296 in osteosarcoma cells and normal cells were compared. LINC01296 knockdown and overexpression were performed in MG63 and HOS8603 osteosarcoma cells by transfecting LINC01296 shRNA and an expression plasmid respectively, followed by investigation of the changes on cell proliferation, migration, apoptosis and cell cycle arrest. Western blotting was used to analyze the changes of cell cycle regulators. Cyclin D1 knockdown and overexpression were carried out to verify the interaction between LINC01296 and cyclin D1. LINC01296 overexpression was demonstrated as a biomarker of osteosarcoma, which was closely correlated with the poor survival of patients with osteosarcoma. A high expression of LINC01296 was observed in osteosarcoma cells, which was closely associated with enhanced proliferation, invasion, and migration of osteosarcoma cells. Cyclin D1 expression was positively correlated with the expression of LINC01296 in osteosarcoma cells. Cyclin D1 knockdown or overexpression played a deterministic role in mediating the effect of LINC01296 on osteosarcoma cells. LINC01296 is an oncogenic lncRNA in osteosarcoma. The proliferation, invasion and migration of osteosarcoma cells could be effectively retarded by inhibition of LINC01296. The cancer?promoting effect of LINC01296 on osteosarcoma was determined by cyclin D1.

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TMPRSS4 induces invasion and proliferation of prostate cancer cells through induction of Slug and cyclin D1.

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TMPRSS4 induces invasion and proliferation of prostate cancer cells through induction of Slug and cyclin D1.

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