Expression of SOCS1 and the downstream targets of its putative tumor suppressor functions in prostate cancer

Abstract

BackgroundSuppressor of cytokine signaling 1 (SOCS1) is considered a tumor suppressor due to frequent epigenetic and micro-RNA-mediated repression of its gene expression in diverse cancers. In prostate cancer (PCa), elevated expression of miR-30d that targets SOCS1 mRNA is associated with increased risk of disease recurrence. SOCS1 can mediate its tumor suppressor functions by diverse mechanisms such as inhibiting the JAK-STAT signaling pathway, promoting the tumor suppressor functions of p53, attenuating MET receptor tyrosine kinase signaling and blocking the oncogenic potential of the cell cycle inhibitor p21CIP1 (p21). Here, we studied the expression of SOCS1 and the downstream targets of its putative tumor suppressor functions (p53, MET and p21) in human PCa specimens to evaluate their significance as markers of disease prognosis.MethodsTissue 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.ResultsSOCS1 showed diffuse staining in the prostatic epithelium. 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). Changes in SOCS1 levels did not significantly associate with those of p53, MET or p21. However, p21 positively correlated with androgen receptor expression (ρ = −0.1388, p = 0.0003). A subset of patients with regional lymph node metastasis, although small in number, showed reduced SOCS1 expression and increased expression of MET and p21.ConclusionsOur findings suggest that evaluating SOCS1 and p21 protein expression in prostatectomy specimens may have a prognostic value in identifying the aggressive disease. Hence, prospective studies with larger numbers of metastatic PCa specimens incorporating clinical correlates such as disease-free and overall survival are warranted.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3141-8) contains supplementary material, which is available to authorized users.

Exosomes of pasteurized milk: potential pathogens of Western diseases

“…miR-155 is upregulated in PCa tissues and cell lines and promotes cell proliferation by targeting annexin 7 [323]. SOCS1 functions as a tumor suppressor in PCa and its expression is reduced in PCa tissue [324]. miR-221-mediated suppression of SOCS1 enhanced cell proliferation and metastasis through in PCa [325].…”

STAT3 and STAT5 Activation in Solid Cancers

“…In STAT3 driven cancers, SOCS3 seems to be the most important negative feedback regulator and mouse models of SOCS3 ablation show strong STAT3 activation [105,[107][108][109][110]. On the other hand, in solid cancers where STAT5 plays a causal role such as liver and prostate cancer, in addition to SOCS3, SOCS1 is frequently inactivated and mouse models of SOCS1 ablation increase both liver and prostate tumorigenesis [111][112][113][114][115][116][117][118]. In addition, SOCS1 and SOCS3 can bind p53 and activate tumor suppressor responses such as senescence and ferroptosis [119][120][121][122][123][124].…”

“…In addition, SOCS1 and SOCS3 can bind p53 and activate tumor suppressor responses such as senescence and ferroptosis [119][120][121][122][123][124]. STAT5 is a potent inducer of the SOCS1-p53-senescence axis and this may explain the better prognosis of cancers with high p-STAT5 [11,119,121,[125][126][127] and the high frequency of SOCS1 inactivation in STAT5-driven cancers [111][112][113][114][115][116][117][118].…”

“…The mechanisms that disable SOCS1 and SOCS3 in human cancers are often epigenetic, mediated either by miRNAs, promoter methylation or protein phosphorylation [113,114,116,117,123,[128][129][130][131][132][133][134][135][136][137]. The SRC family of kinases phosphorylate SOCS1 at Y80, interfering with p53-SOCS1 interactions.…”

Prognostic value of Ki-67 in patients with hypertension and prostate cancer: A real-world study in a Chinese population

“…Prostate cancer is the second most common malignancy, with high mortality among males. [1] In 4 2018, the morbidity and mortality of prostate cancer ranked fourth worldwide for the various forms of cancer, and the mortality is higher for patients with hypertension. Approximately 1.3 million new cases of prostate cancer were diagnosed across the globe in 2018, with 360,000 prostate cancerrelated deaths.…”