The rs3957357C>T SNP in GSTA1 Is Associated with a Higher Risk of Occurrence of Hepatocellular Carcinoma in European Individuals

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.

Acetaminophen‐induced hepatocyte injury: C2‐ceramide and oltipraz intervention, hepatocyte nuclear factor 1 and glutathione S‐transferase A1 changes

“…Moreover, OL has an antioxidant effect at least in part by inducing phase II enzyme and/or an Mn-SOD gene and it resists arachidonic acid-induced mitochondrial oxidative stress by inhibiting ROS production (Kwon, Shin, Cho, & Kim, 2009;). Moreover, Akhdar et al (2016) suggest that decreased expression of GSTA1 is also a marker of advanced and highly aggressive hepatocellular carcinomas. Meanwhile, only 6 μmol/L C2 and 8 μmol/L OL do not cause changes in AST and ALT activity in normal cells.…”

“…It has been demonstrated that GSTA1 rapidly released from the cells to outside, enters the blood circulation and participates in the antioxidant response during hepatic injury Shi et al, 2017). Moreover, Akhdar et al (2016) suggest that decreased expression of GSTA1 is also a marker of advanced and highly aggressive hepatocellular carcinomas. HNF-1 is identified to have a DNA-binding activity that interacts with the promoters of several liver genes and plays an important role in liver-specific transcription (Romero, Ng, & Kirby, 2006).…”

“…In addition, GSTA1 is also associated with the occurrence of a variety of other diseases. Akhdar et al (2016) demonstrated that the TT genotype of GSTA1 was related to hepatocellular carcinoma dedifferentiation, and its occurrence had been found in a survey of European individuals. Therefore, modulation of GSTA1 expression may have important implications for the protection of APAP-induced liver injury.…”

“…6, p12 (Mannervik et al, 2005). Akhdar et al (2016) demonstrated that the TT genotype of GSTA1 was related to hepatocellular carcinoma dedifferentiation, and its occurrence had been found in a survey of European individuals. In addition, GSTA1 is also associated with the occurrence of a variety of other diseases.…”

Effects of GPX3 and GSTA1 Polymorphisms on the Risk of Schizophrenia in Chinese Han Population

“…Besides its through conjugation of reduced form glutathione GSH, GSTA1 can also inactivates quinones [20]. SNP rs3957357 in GSTA1 is just located in the promoter region of GSTA1 genes, and several studies suggested the pathogenic effects of this variant in many disorders [21,22].…”