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

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/β-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.