GSTA2 Promotes Liver Tumor Recurrence after Liver Transplantation through Regulating ROS Metabolism

Abstract

Introduction: Tumor recurrence remains a major obstacle in hepatocellular carcinoma (HCC) recipients after liver transplantation. Our previous studies have indicated that elevated hepatic injury at early-phase after liver transplantation promotes late-phase tumor progression and invasion[1][2]. GSTA2 was identified to be significantly upregulated in early-phase of HCC recipients who developed with tumor recurrence in late-phase. We aimed to investigate the prognostic value of circulating GSTA2 in predicting tumor recurrence after liver transplantation and explore its underlying molecular mechanism.

Methods: Post-transplantation plasma GSTA2 protein of 70 HCC recipients was examined by ELISA analysis. The prognostic value of plasma GSTA2 in predicting tumor recurrence and survival was examined by statistical analyses. The expression level of GSTA2 and ROS-associated genes was examined by real-time RT-PCR. Suppression of GSTA2 in HCC cell lines was established by lentiviral approach. The roles of GSTA2 in regulating HCC proliferation, metastasis and ROS metabolism were studied by in vitro and in vivo functional assays. The effect of GSTA2 in regulating other ROS-associated genes was studied by by RT2 Profiler PCR array.

Results: Higher level of plasma GSTA2 at early-phase after liver transplantation significantly predicted tumor recurrence of HCC recipients (Sensitivity = 0.875; specificity = 0.481; P = 0.031) (Fig.1A). Higher level of plasma GSTA2 was also significantly associated with poor overall (P = 0.041) and disease-free survival (P = 0.024) of HCC recipients (Fig. 1B and 1C). The expression level of hepatic GSTA2 after liver transplantation was significantly correlated with ROS-associated genes such as GPX2 and SOD3. Suppression of GSTA2 in HCC cells significantly inhibited in vitro and in vivo proliferation and metastasis of HCC cells. Upregulation of GSTA2 could compensate H2O2-induced high ROS stress and damage in both normal liver and HCC cells. Alteration of GSTA2 expression in HCC cells could influence the expression level of several ROS-associated genes such as NCF1, SOD3, MT3, MBL2, ALB, TPO and GPX5.

Conclusion: Post-transplantation circulating GSTA2 is a potential biomarker for predicting tumor recurrence and survival of HCC recipients after liver transplantation. Higher level of GSTA2 after liver transplantation could promote tumor recurrence through regulating ROS metabolism.

References:

1. Man K, Lo CM, Xiao JW, Ng KT, Sun BS, Ng IO, Cheng Q, Sun CK, Fan ST. The significance of acute phase small-for-size graft injury on tumor growth and invasiveness after liver transplantation. Ann Surg 2008;247: 1049-57.

2. Man K, Shih KC, Ng KT, Xiao JW, Guo DY, Sun CK, Lim ZX, Cheng Q, Liu Y, Fan ST, Lo CM. Molecular signature linked to acute phase injury and tumor invasiveness in small-for-size liver grafts. Ann Surg 2010;251: 1154-61.