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Interleukin-17 promotes prostate cancer via MMP7-induced epithelial-to-mesenchymal transition.

ABSTRACT: Chronic inflammation has been associated with a variety of human cancers including prostate cancer. Interleukin-17 (IL-17) is a critical pro-inflammatory cytokine, which has been demonstrated to promote development of prostate cancer, colon cancer, skin cancer, breast cancer, lung cancer and pancreas cancer. IL-17 promotes prostate adenocarcinoma with a concurrent increase of matrix metalloproteinase 7 (MMP7) expression in mouse prostate. Whether MMP7 mediates IL-17's action and the underlying mechanisms remain unknown. We generated Mmp7 and Pten double knockout (KO) (Mmp7-/-) mouse model and demonstrated that MMP7 promotes prostate adenocarcinoma through induction of epithelial-to-mesenchymal transition (EMT) in Pten-null mice. MMP7 disrupted E-cadherin/?-catenin complex to upregulate EMT transcription factors in mouse prostate tumors. IL-17 receptor C and Pten double KO mice recapitulated the weak EMT characteristics observed in Mmp7-/- mice. IL-17 induced MMP7 and EMT in human prostate cancer LNCaP, C4-2B and PC-3 cell lines, while small interfering RNA knockdown of MMP7 inhibited IL-17-induced EMT. Compound III, a selective MMP7 inhibitor, decreased development of invasive prostate cancer in Pten single KO mice. In human normal prostates and prostate tumors, IL-17 mRNA levels were positively correlated with MMP7 mRNA levels. These findings demonstrate that MMP7 mediates IL-17's function in promoting prostate carcinogenesis through induction of EMT, indicating IL-17-MMP7-EMT axis as a potential target for developing new strategies in the prevention and treatment of prostate cancer.

SUBMITTER: Zhang Q

PROVIDER: S-EPMC5213194 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Interleukin-17 promotes prostate cancer via MMP7-induced epithelial-to-mesenchymal transition.

Zhang Q Q Liu S S Parajuli K R KR Zhang W W Zhang K K Mo Z Z Liu J J Chen Z Z Yang S S Wang A R AR Myers L L You Z Z

Oncogene 20160704 5

Chronic inflammation has been associated with a variety of human cancers including prostate cancer. Interleukin-17 (IL-17) is a critical pro-inflammatory cytokine, which has been demonstrated to promote development of prostate cancer, colon cancer, skin cancer, breast cancer, lung cancer and pancreas cancer. IL-17 promotes prostate adenocarcinoma with a concurrent increase of matrix metalloproteinase 7 (MMP7) expression in mouse prostate. Whether MMP7 mediates IL-17's action and the underlying m ...[more]

PMID: 27375020

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Project description:A growing body of evidence supports that the epithelial-to-mesenchymal transition (EMT), which occurs during cancer development and progression, has a crucial role in metastasis by enhancing the motility of tumor cells. Transforming growth factor-? (TGF-?) is known to induce EMT in a number of cancer cell types; however, the mechanism underlying this transition process is not fully understood. In this study we have demonstrated that TGF-? upregulates the expression of tumor suppressor protein Par-4 (prostate apoptosis response-4) concomitant with the induction of EMT. Mechanistic investigations revealed that exogenous treatment with each TGF-? isoform upregulates Par-4 mRNA and protein levels in parallel levels of phosphorylated Smad2 and I?B-? increase. Disruption of TGF-? signaling by using ALK5 inhibitor, neutralizing TGF-? antibody or phosphoinositide 3-kinase inhibitor reduces endogenous Par-4 levels, suggesting that both Smad and NF-?B pathways are involved in TGF-?-mediated Par-4 upregulation. NF-?B-binding sites in Par-4 promoter have previously been reported; however, using chromatin immunoprecipitation assay we showed that Par-4 promoter region also contains Smad4-binding site. Furthermore, TGF-? promotes nuclear localization of Par-4. Prolonged TGF-?3 treatment disrupts epithelial cell morphology, promotes cell motility and induces upregulation of Snail, vimentin, zinc-finger E-box binding homeobox 1 and N-Cadherin and downregulation of Claudin-1 and E-Cadherin. Forced expression of Par-4, results in the upregulation of vimentin and Snail expression together with increase in cell migration. In contrast, small interfering RNA-mediated silencing of Par-4 expression results in decrease of vimentin and Snail expression and prevents TGF-?-induced EMT. We have also uncovered a role of X-linked inhibitor of apoptosis protein in the regulation of endogenous Par-4 levels through inhibition of caspase-mediated cleavage. In conclusion, our findings suggest that Par-4 is a novel and essential downstream target of TGF-? signaling and acts as an important factor during TGF-?-induced EMT.

Dataset Information

Interleukin-17 promotes prostate cancer via MMP7-induced epithelial-to-mesenchymal transition.

Publications

Interleukin-17 promotes prostate cancer via MMP7-induced epithelial-to-mesenchymal transition.

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