The Tumor Suppressor SOCS1 Diminishes Tolerance to Oxidative Stress in Hepatocellular Carcinoma

Simple Summary SOCS1 functions as a tumor suppressor in liver cancer and in many other cancers, but the underlying mechanisms are not yet completely understood. Using mice lacking SOCS1 in hepatocytes, we have recently shown that SOCS1 deficiency increases the expression of NRF2. NRF2 is a key protein involved in regulating cellular oxidative stress. Whereas NRF2 is a tumor suppressor in normal cells, it can become an oncoprotein in cancer cells and confer resistance to oxidative stress. In this study, we examined the role of SOCS1 in liver cancer cells exposed to chemicals that induce oxidative stress and carried out a proteomic study. We show that SOCS1 attenuates NRF2 expression in HCC cells and reduces their ability to withstand oxidative stress by modulating diverse proteins involved in redox regulation. Hence, controlling the oxidative stress response is an important tumor suppression mechanism of SOCS1.Abstract SOCS1 is a tumor suppressor in hepatocellular carcinoma (HCC). Recently, we showed that a loss of SOCS1 in hepatocytes promotes NRF2 activation. Here, we investigated how SOCS1 expression in HCC cells affected oxidative stress response and modulated the cellular proteome. Murine Hepa1-6 cells expressing SOCS1 (Hepa-SOCS1) or control vector (Hepa-Vector) were treated with cisplatin or tert-butyl hydroperoxide (t-BHP). The induction of NRF2 and its target genes, oxidative stress, lipid peroxidation, cell survival and cellular proteome profiles were evaluated. NRF2 induction was significantly reduced in Hepa-SOCS1 cells. The gene and protein expression of NRF2 targets were differentially induced in Hepa-Vector cells but markedly suppressed in Hepa-SOCS1 cells. Hepa-SOCS1 cells displayed an increased induction of reactive oxygen species but reduced lipid peroxidation. Nonetheless, Hepa-SOCS1 cells treated with cisplatin or t-BHP showed reduced survival. GCLC, poorly induced in Hepa-SOCS1 cells, showed a strong positive correlation with NFE2L2 and an inverse correlation with SOCS1 in the TCGA-LIHC transcriptomic data. A proteomic analysis of Hepa-Vector and Hepa-SOCS1 cells revealed that SOCS1 differentially modulated many proteins involved in diverse molecular pathways, including mitochondrial ROS generation and ROS detoxification, through peroxiredoxin and thioredoxin systems. Our findings indicate that maintaining sensitivity to oxidative stress is an important tumor suppression mechanism of SOCS1 in HCC.