BACKGROUND & OBJECTIVE: Suppressor of cytokine signaling 1 (SOCS1) is considered a tumor suppressor due to frequent epigenetic repression of the SOCS1 gene in many cancers. Inactivation of SOCS1 also occurs in prostate cancer (PCa) by micro-RNA-mediated repression and gene methylation. SOCS1 has been reported to inhibit IL-6-induced STAT3 activation and downregulate cyclins and cyclin-dependent kinases in PCa cells. However, SOCS1 is not required to control IL-6 signaling in hepatocytes, but is essential to attenuate hepatocyte growth factor (HGF) signaling. The HGF receptor cMET is a receptor tyrosine kinase overexpressed in aggressive and metastatic cancers including PCa. The goals of this study are to determine whether SOCS1 regulates MET signaling in PCa cells and to elucidate the regulatory functions of SOCS1 in the prostatic epithelium using mice lacking the Socs1 gene in the prostate gland.
METHODS: PCa cell lines PC3 and DU145 were stably transduced with SOCS1 or the control lentiviral vector. These cells were stimulated with HGF, and proliferation, cell migration, invasion and downstream signaling events were assessed. These cells were injected subcutaneously into the flanks or orthotopically into the prostate glands of NOD.scid.gamma mice and tumors growth was monitored. Tumor sections were evaluated for cell proliferation. Prostate-specific Socs1-null mice were generated by crossing Socs1-floxed (Socs1fl/lfl) mice with probasin-Cre (PbCre) mice. Prostate glands of SOCS1-deficient mice were collected at different ages and examined by histopathology for ultrastructural changes.
RESULTS: In response to HGF stimulation, SOCS1-expressing cells showed reduced proliferation, migration and invasion of the collagen matrix. In vivo, SOCS1-expressing PCa cells showed significantly reduced tumor growth, and reduced metastatic spread in the orthotopic tumor model. Surprisingly, the SOCS1-expressing DU145 and PC3 tumors showed increased matrix deposition and elevated numbers of myofibroblasts. Genetic ablation of SOCS1 in the prostate gland of mice caused differential hyperproliferation of prostatic epithelium in certain lobes that resembled prostatic intraepithelial neoplasia (PIN).
CONCLUSIONS: The tumor suppressor function of SOCS1 in the prostate gland is mediated, at least partly, from negative regulation of MET signaling. SOCS1 plays a crucial role in controlling the proliferation of prostatic epithelial cells.