Glutathione S-transferase A2 (GSTA2) Promotes Hepatocellular Carcinoma Recurrence After Liver Transplantation Through Modulating Reactive Oxygen Species Metabolism

Abstract

BackgroundAn inevitable hepatic injury at the early phase after liver transplantation vitally affects the late phase hepatocellular carcinoma (HCC) recurrence. However, their linkage and underlying risk factors of HCC recurrence are unclear. This study aimed to clarify the clinical impact and functional roles of glutathione S-transferase A2 (GSTA2) in affecting HCC recurrence after liver transplantation.MethodsExpression significance and prognostic value of hepatic and circulating GSTA2 in HCC recipients were examined. The polymorphism of GSTA2 transcript was analysed by Sanger sequencing. The functions and molecular mechanisms of GSTA2 in the proliferation and metastasis of HCC were characterized by molecular, cellular and animal experiments. ResultsThe GSTA2 expression was significantly correlated with the early phase hepatic and systemic injury and reactive oxygen species (ROS) level after liver transplantation. Importantly, the level of the early phase circulating GSTA2 protein was a significant predictor of HCC recurrence and survival of HCC recipients. Heterogeneous single nucleotide polymorphism at G335C of GSTA2 was significantly associated with poor survival of HCC recipients. The GSTA2 expression was positively correlated with the aggressiveness of HCCs. Overexpression of GSTA2, by endogenous or exogenous approaches, could enhance the proliferation and invasion of HCCs through activating epithelial-mesenchymal-transition promoting proteins. Targeted inhibition of GSTA2 remarkably suppressed the proliferation and metastasis of HCCs. Increased level of GSTA2 could compensate the H2O2-induced ROS stress and therefore protect the HCC cells from damage. Alteration of GSTA2 expression in HCC cells could influence the activation of ROS-associated JNK and AKT signaling pathways and the expression of ROS-associated genes in responding to the H2O2 condition. ConclusionsOur research discovered GSTA2 to be the significant risk factor of HCC recurrence via providing a favorable ROS environment for HCC to survival and progress. This study presents a novel functional biomarker for combating HCC recurrence after liver transplantation.