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Background   SOCS1  and  SOCS3  genes are considered tumor suppressors in hepatocellular carcinoma (HCC) due to frequent epigenetic repression. Consistent with this notion, mice lacking SOCS1 or SOCS3 show increased susceptibility to diethylnitrosamine (DEN)-induced HCC. As SOCS1 and SOCS3 are important regulators of cytokine and growth factor signaling, their loss could activate oncogenic signaling pathways. Therefore, we examined the correlation between  SOCS1 /S OCS3  and key oncogenic signaling pathway genes as well as their prognostic significance in HCC.    Methods  The Cancer Genome Atlas dataset on HCC comprising clinical and transcriptomic data was retrieved from the cBioportal platform. The correlation between the expression of  SOCS1  or  SOCS3  and oncogenic pathway genes was evaluated using the GraphPad PRISM software. The inversely correlated genes were assessed for their impact on patient survival using the UALCAN platform and their expression quantified in the regenerating livers and DEN-induced HCC tissues of mice lacking  Socs1  or  Socs3 . Finally, the Cox proportional hazards model was used to evaluate the predictive potential of  SOCS1  and  SOCS3  when combined with the genes of select oncogenic signaling pathways.    Results   SOCS1  expression was comparable between HCC and adjacent normal tissues, yet higher  SOCS1  expression predicted favorable prognosis. In contrast,  SOCS3  expression was significantly low in HCC, yet it lacked predictive potential. The correlation between  SOCS1  or  SOCS3  expression and key genes of the cell cycle, receptor tyrosine kinase, growth factor and MAPK signaling pathways were mostly positive than negative. Among the negatively correlated genes, only a few showed elevated expression in HCC and predicted survival. Many PI3K pathway genes showed mutual exclusivity with  SOCS1  and/or  SOCS3  and displayed independent predictive ability. Among genes that negatively correlated with  SOCS1  and/or  SOCS3 , only  CDK2  and  AURKA  showed corresponding modulations in the regenerating livers and DEN-induced tumors of hepatocyte-specific  Socs1  or  Socs3  deficient mice and predicted patient survival. The Cox proportional hazards model identified the combinations of  SOCS1  or  SOCS3  with  CXCL8  and  DAB2  as highly predictive.    Conclusions   SOCS1  expression in HCC has an independent prognostic value whereas  SOCS3  expression does not. The predictive potential of  SOCS1  expression is increased when combined with other oncogenic signaling pathway genes.

Prognostic significance of SOCS1 and SOCS3 tumor suppressors and oncogenic signaling pathway genes in hepatocellular carcinoma