SOCS1 Deficiency Promotes Hepatocellular Carcinoma via SOCS3-Dependent CDKN1A Induction and NRF2 Activation

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Abstract
SOCS1 deficiency, which increases susceptibility to hepatocellular carcinoma (HCC), promotes CDKN1A expression in the liver. High CDKN1A expression correlates with disease severity in many cancers. Here, we demonstrate a crucial pathogenic role of CDKN1A in diethyl nitrosamine (DEN)-induced HCC in SOCS1-deficient mice. Mechanistic studies on DEN-induced genotoxic response revealed that SOCS1-deficient hepatocytes upregulate SOCS3 expression, SOCS3 promotes p53 activation, and Cdkn1a induction that were abolished by deleting either Socs3 or Tp53. Previous reports implicate CDKN1A in promoting oxidative stress response mediated by NRF2, which is required for DEN-induced hepatocarcinogenesis. We show increased induction of NRF2 and its target genes in SOCS1-deficient livers following DEN treatment that was abrogated by the deletion of either Cdkn1a or Socs3. Loss of SOCS3 in SOCS1-deficient mice reduced the growth of DEN-induced HCC without affecting tumor incidence. In the TCGA-LIHC dataset, the SOCS1-low/SOCS3-high subgroup displayed increased CDKN1A expression, enrichment of NRF2 transcriptional signature, faster disease progression, and poor prognosis. Overall, our findings show that SOCS1 deficiency in hepatocytes promotes compensatory SOCS3 expression, p53 activation, CDKN1A induction, and NRF2 activation, which can facilitate cellular adaptation to oxidative stress and promote neoplastic growth. Thus, the NRF2 pathway represents a potential therapeutic target in SOCS1-low/SOCS3-high HCC cases.
Funding Information
  • Canadian Institutes of Health Research (PJT-153174, PJT-162246, JSPS KAKENHI 19K07514, 21H05044, AMED-CREST 21gm1110009, AMED-Moonshot 21zf0127003h0001, PJT-153174, PJT-162246)
  • graduate scholarships from the FRQNT (PJT-153174, PJT-162246, JSPS KAKENHI 19K07514, 21H05044, AMED-CREST 21gm1110009, AMED-Moonshot 21zf0127003h0001, PJT-153174, PJT-162246)
  • Canadian Institutes of Health Research (PJT-153174, PJT-162246, JSPS KAKENHI 19K07514, 21H05044, AMED-CREST 21gm1110009, AMED-Moonshot 21zf0127003h0001, PJT-153174, PJT-162246)

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