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 (Mmp7−/− in abbreviation) 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 up-regulate EMT transcription factors in mouse prostate tumors. IL-17 receptor C and Pten double knockout 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 siRNA knockdown of MMP7 inhibited IL-17-induced EMT. Compound III, a selective MMP7 inhibitor, decreased development of invasive prostate cancer in Pten single knockout 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 potential targets for developing new strategies in the prevention and treatment of prostate cancer.

EGFR‐mediated matrix metalloproteinase‐7 up‐regulation promotes epithelial‐mesenchymal transitionviaERK1‐AP1 axis during ovarian endometriosis progression

“…This also indicates that MMP-7 acts as an upstream signal for EMT responses. Consistent with our findings, MMP-7 knockout mice exhibited decreased EMT and metastasis in a mouse model of prostate carcinoma (38). Similar to the present report, other studies have also demonstrated MMP-7-mediated cleavage of cell-cell adherent proteins including E-cadherin and zona occludin-1 in different cancer models (14,29).…”

“…Similar to the present report, other studies have also demonstrated MMP-7-mediated cleavage of cell-cell adherent proteins including E-cadherin and zona occludin-1 in different cancer models (14,29). Furthermore, MMP-7 disrupts the E-cadherin-b-catenin complex, causing the release of b-catenin, which also promotes EMT in human prostate cancer cells (38).…”

Phospholipase Cδ1 suppresses cell migration and invasion of breast cancer cells by modulating KIF3A-mediated ERK1/2/β- catenin/MMP7 signalling

“…MMP7 is a matrix metallopeptidase that is involved in tumour progression by influencing cell invasion, metastasis, and the epithelial-to-mesenchymal transition [21–23]. It is well known that MMP7 is a downstream target of the Wnt/β-catenin signalling pathway that is activated in multiple cancers including breast cancers [24].…”

Inflammatory cytokines IL-17 and TNF-α up-regulate PD-L1 expression in human prostate and colon cancer cells

“…It has been demonstrated that certain pro-inflammatory factors can up-regulate PD-L1 expression, including interferon-γ (IFN-γ), tumor necrosis factor – α (TNF-α), lipopolysaccharide, granulocyte-monocyte colony stimulating factor, vascular endothelial growth factor, interleukin-10 (IL-10), and IL-4, with IFN-γ being the most potent inducer [16]. Interleukin-17 (IL-17, also called IL-17A) is a key pro-inflammatory cytokine that has been shown to promote prostate and colon cancer development [17–20]. IL-17 and TNF-α have been shown to cooperate functionally to induce expression of down-stream genes [21].…”