TrxR1, Gsr, and oxidative stress determine hepatocellular carcinoma malignancy

Abstract

Thioredoxin reductase-1 (TrxR1)-, glutathione reductase (Gsr)-, and Nrf2 transcription factor-driven antioxidant systems form an integrated network that combats potentially carcinogenic oxidative damage yet also protects cancer cells from oxidative death. Here we show that although unchallenged wild-type (WT), TrxR1-null, or Gsr-null mouse livers exhibited similarly low DNA damage indices, these were 100-fold higher in unchallenged TrxR1/Gsr–double-null livers. Notwithstanding, spontaneous cancer rates remained surprisingly low in TrxR1/Gsr-null livers. All genotypes, including TrxR1/Gsr-null, were susceptible to N-diethylnitrosamine (DEN)-induced liver cancer, indicating that loss of these antioxidant systems did not prevent cancer cell survival. Interestingly, however, following DEN treatment, TrxR1-null livers developed threefold fewer tumors compared with WT livers. Disruption of TrxR1 in a marked subset of DEN-initiated cancer cells had no effect on their subsequent contributions to tumors, suggesting that TrxR1-disruption does not affect cancer progression under normal care, but does decrease the frequency of DEN-induced cancer initiation. Consistent with this idea, TrxR1-null livers showed altered basal and DEN-exposed metabolomic profiles compared with WT livers. To examine how oxidative stress influenced cancer progression, we compared DEN-induced cancer malignancy under chronically low oxidative stress (TrxR1-null, standard care) vs. elevated oxidative stress (TrxR1/Gsr-null livers, standard care or phenobarbital-exposed TrxR1-null livers). In both cases, elevated oxidative stress was correlated with significantly increased malignancy. Finally, although TrxR1-null and TrxR1/Gsr-null livers showed strong Nrf2 activity in noncancerous hepatocytes, there was no correlation between malignancy and Nrf2 expression within tumors across genotypes. We conclude that TrxR1, Gsr, Nrf2, and oxidative stress are major determinants of liver cancer but in a complex, context-dependent manner.

A Novel Signature Based on mTORC1 Pathway in Hepatocellular Carcinoma

“…Singh et al found that ETF1, CNOT6 , and XRN1 gene in HepG2 cells led to significant alteration in stability of specific mRNAs, and this mechanism may hold novel cancer therapeutic targets [ 19 ]. In another research, McLoughlin concluded that GSR, TRXR1, NRF2 , and oxidative stress determined hepatocellular carcinoma malignancy [ 20 ]. Lee's et al study [ 21 ] found that HSPD1 was downregulated during early apoptosis of the hepatoma cell mediated by Paeoniae Radix.…”

Idenfication of a novel signature based on mTORC1 pathway for hepatocellular carcinoma.

“…Singh et al found that ETF1, CNOT6 and XRN1 gene in HepG2 cell led to significant alteration in stability of specific mRNAs and this mechanism may hold novel cancer therapeutic targets [19]. In another research, McLoughlin concluded that GSR, TRXR1, NRF2 and oxidative stress determined hepatocellular carcinoma malignancy [20]. Lee's study [21] found that HSPD1 was down-regulated during early apoptosis of the hepatoma cell mediated by Paeoniae Radix.…”

Co-expression Network Identification and Clinical Prognostic Evaluation of Hub Genes in Head and Neck Squamous Cell Carcinoma

“…As a signaling molecule, ROS can activate carcinogenic pathways. The thioredoxin system is the main category of mammalian antioxidant systems [35]. It comprises thioredoxin, thioredoxin reductase, and nicotinamide adenine dinucleotide phosphate and reduced (NADPH) [36,37].…”