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

• Published in: Cancers Vol. 15; no. 3; p. 905
• Main Authors: Khan, Md Gulam Musawwir, Boufaied, Nadia, Yeganeh, Mehdi, Kandhi, Rajani, Petkiewicz, Stephanie, Sharma, Ankur, Yoshimura, Akihiko, Ferbeyre, Gerardo, Labbé, David P, Ramanathan, Sheela, Ilangumaran, Subburaj
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 31.01.2023; MDPI
• Subjects: Animal models; CDKN1A; Cyclin-dependent kinases; Cytokines; Development and progression; Gene expression; Genetic aspects; Genotoxicity; Growth factors; Health aspects; Hepatocellular carcinoma; Hepatocytes; Hepatoma; Kinases; Liver cancer; Medical prognosis; NRF2; NRF2 protein; Oxidative stress; p53; p53 Protein; Physiological aspects; Protein expression; Proteins; SOCS1; SOCS3; Software; Survival analysis; Therapeutic applications; Therapeutic targets; Transcriptional coactivators; Tumors; Canada; United States > US; mouse models; SOCS3; CDKN1A; SOCS1; NRF2; TCGA-LIHC; hepatocellular carcinoma; oxidative stress; p53
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers15030905

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 induction that were abolished by deleting either or . 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 or . Loss of SOCS3 in SOCS1-deficient mice reduced the growth of DEN-induced HCC without affecting tumor incidence. In the TCGA-LIHC dataset, the -low/ -high subgroup displayed increased 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 -low/ -high HCC cases.