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.Oncogene advance online publication, 4 July 2016; doi:10.1038/onc.2016.240.
Oncogene. 2016 Jul 04 [Epub ahead of print]
Q Zhang, S Liu, K R Parajuli, W Zhang, K Zhang, Z Mo, J Liu, Z Chen, S Yang, A R Wang, L Myers, Z You
Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA., Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA., Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA., Department of Computer Science and Biostatistics Facility of RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA, USA., Department of Computer Science and Biostatistics Facility of RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA, USA., Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA., Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA., Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA., Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA., Department of Pathology and Laboratory Medicine, Tulane University, New Orleans, LA, USA., Department of Biostatistics and Bioinformatics, Tulane University, New Orleans, LA, USA., Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA.