title: 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/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.
authors.affiliation: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: K R
authors.initials: KR
authors.lastname: Parajuli
authors.affiliation: Department of Computer Science and Biostatistics Facility of RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA, USA.
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Computer Science and Biostatistics Facility of RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA.|Department of Obstetrics and Gynecology, Shijiazhuang Maternal and Child Health Care Hospital, Shijiazhuang, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Mo
authors.affiliation: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA.|Department of Obstetrics and Gynecology, Shijiazhuang Maternal and Child Health Care Hospital, Shijiazhuang, China.
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA.|Department of Thoracic Surgery, Affiliated Hospital of North China University of Science and Technology, Tangshan, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA.|Department of Urology, The Third Hospital of Hebei Medical University, Shijiazhuang, China.
authors.forename: S
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University, New Orleans, LA, USA.
authors.forename: A R
authors.initials: AR
authors.lastname: Wang
authors.affiliation: Department of Biostatistics and Bioinformatics, Tulane University, New Orleans, LA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Myers
authors.affiliation: Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA, USA.|Department of Orthopaedic Surgery, Tulane University, New Orleans, LA, USA.|Tulane Cancer Center and Louisiana Cancer Research Consortium, Tulane University, New Orleans, LA, USA.|Tulane Center for Stem Cell Research and Regenerative Medicine, Tulane University, New Orleans, LA, USA.|Tulane Center for Aging, Tulane University, New Orleans, LA, USA.
authors.forename: Z
authors.identifier: 0000-0001-5048-2229
authors.initials: Z
authors.lastname: You
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D007249:Inflammation / Q000473:pathology; D020381:Interleukin-17 / Q000378:metabolism*; D008297:Male; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism*; D051379:Mice; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction
chemical_list: D020381:Interleukin-17; D020783:Matrix Metalloproteinase 7