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

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.

Silica nanoparticle conjugation with gallic acid towards enhanced free radical scavenging capacity and activity on osteosarcoma cells in vitro

“…After incubation, the cells were gently washed with live cell imaging solution, and a blank measurement was conducted. A screening of the ROS trigger tert -butyl-hydroperoxide (TBHP) 47 was conducted using concentrations of 0.002, 0.1, 0.2, and 0.5 mM. Among these, a concentration of 0.2 was selected for further analysis.…”

SOCS1 expression in cancer cells: potential roles in promoting antitumor immunity

“…Data shown in A–C were generated from experiments approved by the Université de Sherbrooke Ethics Committee for Animal Care and Use. (E, F) Proteomes of Hepa-Vector and Hepa-SOCS1 cells were studied by tandem mass spectrometry, as detailed in ( 65 ) Reference. Proteins that were significantly upregulated in Hepa-SOCS1 cells (≥ 0.5 fold change and ≥1.3 -log10 p-Value; 551 proteins) were subjected to gene ontology analysis.…”

“…We have observed that Hepa-SOCS1 cells displayed marked alterations in the constituents of spliceosome, a multiprotein complex involved in processing RNA transcripts to mediate splicing, remove intronic sequences and generate mRNA for translation ( 77 ). In a recent study using shotgun proteomics employing data-independent acquisition, we observed that SOCS1-expressing Hepa cells showed upregulation of several hundred proteins ( 65 ). Pathway analysis of significantly upregulated proteins revealed that these proteins are enriched for the biological processes related to RNA splicing, mRNA processing, non-coding RNA (ncRNA) processing, rRNA processing and ribonucleoprotein complex biogenesis ( Figure 1E ), and showed significant enrichment within the cellular compartments of spliceosome, U2-spliceosome, catalytic step 2 spliceosome, nuclear speck and chromosomal region ( Figure 1F ), suggesting a profound impact of SOCS1 on pre-mRNA processing that could generate alternate splice forms.…”