Abstract
The SOCS1 (Suppressor Of Cytokine Signalling 1) protein is considered a tumour suppressor. Notably, the SOCS1 gene is frequently silenced in cancer by hypermethylation of its promoter. Besides blocking inflammation, SOCS1 tumour suppressor activity involves Met receptor inhibition and enhancement of p53 tumour suppressor activity. However, the role of SOCS1 in colorectal cancer (CRC) remains understudied and controversial. Here, we investigated SOCS1 relevance for CRC by querying gene expression datasets of human CRC specimens from The Cancer Genome Atlas (TCGA), and by SOCS1 gain/loss-of-function analyses in murine and human colon carcinoma cells. Our results show that SOCS1 mRNA levels in tumours were more often elevated than reduced with respect to matched adjacent normal tissue of CRC specimens (n = 41). The analysis of TCGA dataset of 431 CRC patients revealed no correlation between SOCS1 expression and overall survival. Overexpression of SOCS1 in CRC cells triggered cell growth enhancement, anchorage-independent growth and resistance to death stimuli, whereas knockdown of SOCS1 reduced these oncogenic features. Moreover, SOCS1 overexpression in mouse CT26 cells increased tumourigenesis in vivo. Biochemical analyses showed that SOCS1 pro-oncogenic activity correlated with the down-modulation of STAT1 expression. Collectively, these results suggest that SOCS1 may work as an oncogene in CRC.
Highlights
The protein SOCS1 was first uncovered as a negative-feed back regulator of cytokine receptors that signal via the Janus family of tyrosine kinases (JAK) and the signal transducers and activators of transcription (STAT) proteins
The value of SOCS1 expression as a predictor of human CRC progression has not been extensively explored. This prompted us to analyse SOCS1 gene expression in human CRC based on publically available The Cancer Genome Atlas (TCGA) HiSeq RNA sequencing (RNA-Seq) gene expression profiling datasets of human CRC samples[27]
There was no significant difference in SOCS1 mRNA expression between normal and tumour tissues based on a Wilcoxon matched-pairs signed rank test (Fig. 1B, Median difference in SOCS1 mRNA = 11.68, P = 0 .0512)
Summary
The protein SOCS1 was first uncovered as a negative-feed back regulator of cytokine receptors that signal via the Janus family of tyrosine kinases (JAK) and the signal transducers and activators of transcription (STAT) proteins. SOCS1 increases p53 phosphorylation (Ser15), DNA binding and transcriptional activity by forming a ternary complex with the DNA damage-regulated kinases ATM or ATR, which is critical for p53-dependent activation of genes involved in DNA repair, senescence and apoptosis[12] These findings provide compelling evidence that SOCS1 works as a dominant tumour suppressor in HCC and underlie the molecular mechanisms involved. Two recently published studies have so far probed the abundance of SOCS1 mRNA or protein in relatively small cohorts of human CRC samples[22,23]. An obvious increase in size of the colonies formed by SOCS1-expressing SW620 cells compared to control cells was not accounted for Overall, these limited numbers of studies have not yet settled whether or not SOCS1 is working as a tumour suppressor or as an oncogene in CRC. We provide the first experimental evidence, both in vitro and in vivo, that SOCS1 fosters pro-oncogenic features in CRC cells
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