Interleukin-17 (IL-17) is a key cytokine in inflammation, which has been shown to play critical roles in development of prostate cancer, skin cancer, colon cancer, and breast cancer. We have previously demonstrated that IL-17 promotes prostate carcinogenesis, accompanied with increased expression of matrix metalloproteinase 7 (MMP7) in the mouse prostate. The purpose of the present study was to determine whether MMP7 mediates IL-17's action and the underlying mechanisms. Mmp7 knockout (Mmp7−/−) mice were crossbred with phosphatase and tensin homolog (Pten) conditional knockout mice (Ptenpc-/−, prostate-specific through probasin promoter-driven Cre recombinase). The prostate tumor phenotypes were analyzed among Mmp7+/+;Ptenpc-/−, Mmp7+/−;Ptenpc-/−, and Mmp7−/−;Ptenpc-/− mice. MMP7-overexpression or MMP7 knockdown using small interfering RNA (siRNA) was generated in human prostate cancer LNCaP and C4-2B cell lines to explore the molecular mechanisms of MMP7's actions. We found that Mmp7−/−;Ptenpc-/− mice displayed prostates that were smaller than Mmp7+/+;Ptenpc-/− or Mmp7+/−;Ptenpc-/− mice. Mmp7−/−;Ptenpc-/− mice developed a reduced number of invasive prostate adenocarcinomas with lower rate of cellular proliferation and higher rate of apoptosis than Mmp7+/+;Ptenpc-/− or Mmp7+/−;Ptenpc-/− mice. In addition, the invasiveness of prostate tumor cells isolated from Mmp7−/−;Ptenpc-/− mice was significantly reduced compared to those isolated from Mmp7+/+;Ptenpc-/− mice in Matrigel® invasion assays. Expression of the epithelial-to-mesenchymal transition (EMT) markers, such as β-catenin, vimentin, Snail, and Slug, was dramatically reduced in Mmp7−/−;Ptenpc-/− mice compared to Mmp7+/+;Ptenpc-/− or Mmp7+/−;Ptenpc-/− mice. In contrast, expression of the epithelial markers such as E-cadherin and claudin was increased in Mmp7−/−;Ptenpc-/− mice compared to Mmp7+/+;Ptenpc-/− or Mmp7+/−;Ptenpc-/− mice. MMP7 cleaved E-cadherin and disrupted E-cadherin/β-catenin complex to increase cytoplasmic and nuclear β-catenin levels in the prostate cancer cells, thus up-regulating EMT transcription factors. In addition, IL-17 receptor C (Il-17rc) and Pten double knockout (Il-17rc−/−;Ptenpc-/−) mice echoed the reduction of EMT in Mmp7−/−;Ptenpc-/− mice, compared to Il-17rc+/+;Ptenpc-/− mice. Further, IL-17 treatment induced MMP7 expression in LNCaP and C4-2B cells, leading to increased expression of EMT markers. In contrast, MMP7 knockdown inhibited IL-17-induced expression of EMT markers. Taken together, our results demonstrate that MMP7 mediates IL-17's function in promoting prostate carcinogenesis through induction of EMT.

This work was partially funded by National Institutes of Health (R01CA174714 and P20GM103518), Department of Defense (W81XWH-14-1-0050, W81XWH-14-1-0149, W81XWH-14-1-0458, and W81XWH-15-1-0444), and Tulane's Institute of Integrated Engineering for Health and Medicine.

Citation Format: Qiuyang Zhang, Sen Liu, Keshab Parajuli, Zongbing You. Interleukin-17 acts through MMP7 to promote prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5171.