Abstract
Glutathione S-transferases (GSTs) detoxify toxic molecules by conjugation with reduced glutathione and regulate cell signaling. Single nucleotide polymorphisms (SNPs) of GST genes have been suggested to affect GST functions and thus to increase the risk of human hepatocellular carcinoma (HCC). As GSTA1 is expressed in hepatocytes and the rs3957357C>T (TT) SNP is known to downregulate GSTA1 mRNA expression, the aims of this study were: (i) to explore the relationship between the TT SNP in GSTA1 and the occurrence of HCC; (ii) to measure GSTA1 mRNA expression in HCCs. For that purpose, we genotyped non-tumor-tissue-derived DNA from 48 HCC patients and white-blood-cell-derived DNA from 37 healthy individuals by restriction fragment length polymorphism (RFLP). In addition, expression of GSTA1 mRNA was assessed by real-time PCR in 18 matching pairs of HCCs and non-tumor livers. Survival analysis was performed on an annotated microarray dataset containing 247 HCC patients (GSE14520). The GSTA1 TT genotype was more frequent in HCC than in non-HCC patients (27% versus 5%, respectively), suggesting that individuals carrying this genotype could be associated with 2-fold higher risk of developing HCCs (odds ratio = 2.1; p = 0.02). Also, we found that GSTA1 mRNA expression was lower in HCCs than in non-tumor livers. HCCs expressing the highest GSTA1 mRNA levels were the smallest in size (R = -0.67; p = 0.007), expressed the highest levels of liver-enriched genes such as ALB (albumin, R = -0.67; p = 0.007) and COL18A1 (procollagen type XVIII, R = -0.50; p = 0.03) and showed the most favorable disease-free (OR = 0.54; p<0.001) and overall (OR = 0.56; p = 0.006) outcomes. Moreover, GSTA1 was found within a 263-gene network involved in well-differentiated hepatocyte functions. In conclusion, HCCs are characterized by two GSTA1 features: the TT SNP and reduced GSTA1 gene expression in a context of hepatocyte de-differentiation.
Highlights
Hepatocellular carcinoma (HCC) is the third cause of cancer-related death in the world [1]
We found that individuals homozygous for the the rs3957 357C>T (TT) genotype of GSTA1 were associated with a 2-fold increase in the risk of developing HCCs and that low GSTA1 gene expression occurs in poorly-differentiated tumors showing a bad clinical outcome
Analysis of the HapMap data showed that the 7 single nucleotide polymorphisms (SNPs) known in GSTA1 were in Linkage disequilibrium (LD) in European individuals (Fig 1A)
Summary
Hepatocellular carcinoma (HCC) is the third cause of cancer-related death in the world [1]. Case-control and cohort studies have suggested the association of single nucleotide polymorphisms (SNPs) in the glutathione S-transferase (GST) gene with an increased risk of occurrence of HCC [4, 5]. GSTs belong to the family of intracellular isoenzymes that mediate the conjugation of reduced glutathione to exogenous or endogenous compounds. Oxidative stress products, prostaglandins, chemical carcinogens and therapeutic drugs are detoxified by GSTs [6]. The nucleophilic attack of reduced glutathione on electrophilic substrates, catalyzed by GST enzymes, represents a defense mechanism in the cell. Glutathione conjugation reduces the toxic effects of strongly reactive products on proteins and DNA [6]. One of the roles of GSTs is to protect DNA against oxidative damage, which may lead to mutations, and in consequence, favor carcinogenesis [6]. It has been shown that GSTs play important roles in regulating signaling pathways in a catalytic-independent manner through direct interaction with kinases, such as c-jun N-terminal kinase (JNK) and apoptosis signalregulating kinase 1 (ASK1) to modulate their phosphorylation activities [7]
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