SOCS1 and SOCS3 are considered tumor suppressors in the liver. Mice lacking either SOCS1 or SOCS3 show increased susceptibility to hepatocellular carcinoma (HCC). Previously we have shown that SOCS1 attenuates the oncogenic potential of p21CIP1/WAF1 (p21) via ubiquitination and proteasomal degradation. Contrary to SOCS1, SOCS3 has been reported to promote p21 expression. However, both SOCS1 and SOCS3 can activate p53, a transcriptional activator of Cdkn1a that encodes p21. p21 promotes oncogenesis via several mechanisms including activation of NRF2, a transcriptional factor that induces cytoprotective genes against oxidative stress. The goal of this study is to understand the disparate regulation of p21 by SOCS1 and SOCS3, and to elucidate their role in p21-dependent oncogenic processes in HCC.
We generated mice lacking SOCS1, SOCS3 or both in the liver, and evaluated their susceptibility to HCC induction by diethylnitrosamine (DEN). Hepatocyte-specific SOCS1- or SOCS3-deficient mice showed increased susceptibility to DEN-induced HCC, but the loss of both SOCS proteins attenuated HCC progression despite increased STAT3 activation caused by SOCS3 deficiency. We show that elevated p21 expression and increased p53 phosphorylation in SOCS1-deficent liver are mediated by SOCS3. Besides Cdkn1a, certain other p53 target genes are induced in the SOCS1-deficient liver in a SOCS3-dependent manner. Loss of p21 in SOCS1-deficient livers attenuated the induction of Nfe2l2 coding for NRF2 and its target genes, and diminished HCC susceptibility. Overall, our findings indicate that loss of SOCS1 leads to a compensatory increase in SOCS3 expression presumably to attenuate cytokine signaling, but SOCS3 appears to exacerbate the paradoxical oncogenic functions of p21 by promoting the NRF2-mediated antioxidant functions, thereby contributing to HCC pathogenesis.