BACKGROUND & OBJECTIVE: Epigenetic and micro-RNA-mediated repression of the Suppressor of cytokine signaling 1 (SOCS1) gene occurs in diverse cancers, and hence is SOCS1 is considered a tumor suppressor. Elevated expression of miR-30d that targets SOCS1 mRNA is associated with increased risk of prostate cancer (PCa) recurrence. The tumor suppressor function of SOCS1 has been attributed to its ability to inhibit the JAK-STAT signaling pathway, promote the tumor suppressor functions of p53, attenuate MET receptor tyrosine kinase signaling and block the paradoxical oncogenic role of the cell cycle inhibitor p21CIP1 (p21). The objective of this study is to determine which of these tumor suppressor mechanisms of SOCS1 predominates in PCa by evaluating the expression of SOCS1 along with the mediators of its tumor suppressor functions - p53, MET and p21 - in human PCa specimens.
METHODS: Tissue microarrays were constructed of 78 archived prostatectomy specimens that were grouped according to the recommendations of the International Society of Urological Pathology (ISUP) based on the Gleason patterns. SOCS1, p53, MET and p21 protein expression were evaluated by immunohistochemical staining alongside the common prostate cancer-related markers Ki67, prostein and androgen receptor. Statistical correlations between the staining intensities of these markers and ISUP grade groups, local invasion or lymph node metastasis were evaluated. Gene expression of SOCS1, p53, MET and p21, and the correlation between these values were also evaluated using The Cancer Genome Atlas (TCGA) database on PCa.
RESULTS: The prostatic epithelium showed diffuse staining for SOCS1. The SOCS1 staining intensity correlated inversely with the ISUP grade groups (ρ =-0.4687, p <0.0001) and Ki67 (ρ=-0.2444, p=0.031), and positively with prostein (ρ=0.3511, p=0.0016). Strikingly, SOCS1 expression levels did not show any correlation with those of p53, MET or p21. However, a positively correlation was observed between p21 and androgen receptor expression (ρ=-0.1388, p=0.0003). A subset of patients with regional lymph node metastasis showed reduced SOCS1 expression along with increased expression of MET and p21.
CONCLUSIONS: Evaluating SOCS1 and p21 protein expression in prostatectomy specimens may have a prognostic value in identifying the aggressive disease. However, this would require development of highly specific and sensitive clinical grade SOCS1 antibodies, and testing them on a larger number of metastatic PCa specimens.