The role of glutathione peroxidase 3 (GPx3) : bridging graft injury and tumor invasiveness

Abstract

Background and Objective: Severe inflammation resulted from small-for-size liver graft injury provides favorable environment for tumor growth. The oxidative stress not only accelerates the inflammatory response, but also stimulates the proliferation of cancer cells. Therefore, attenuating oxidative stress after liver surgery may not only ameliorate liver injury, but also suppress tumor growth and metastasis. Glutathione peroxidase 3 (GPx3) is an anti-oxidant which has been reported to be down-regulated in several types of cancer. Here, we aimed to investigate the clinical significance of GPx3 and characterize the role of GPx3 in liver graft injury and hepatocellular carcinoma (HCC). Furthermore, we intended to explore the therapeutic value of GPx3 using hiPSC-MSCs as a delivery vehicle in hepatic ischemia-reperfusion injury and HCC.

Materials and methods: To investigate the clinical significance of GPx3, the HCC patients underwent liver transplantation (106 recipients) or hepatectomy (113 patients) were recruited to study the correlation of GPx3 with clinical parameters. To explore the mechanism of GPx3 in liver graft injury, simulated IR injury model and rat liver transplantation model were applied. To examine the effect of GPx3 on HCC, rGPx3 administration and forced-expression of GPx3 within HCC cells were performed in vitro and in vivo. To explore the therapeutic value of GPx3, engineered hiPSC-MSCs delivering GPx3 was established and applied in mice hepatic IR injury model and nude mice liver cancer model.

Results: I. The role of GPx3 in graft injury.

The intra-graft GPx3 expression was significantly down-regulated in small-for-size graft accompanied with severe graft injury in a rat liver transplantation model. Clinically, the lower plasma GPx3 was mainly observed in the recipients with small-for-size liver graft. Furthermore, the lower plasma GPx3 significantly correlated with higher tumor recurrence post-transplantation. The down-regulation of GPx3 was associated with hepatic senescence in small-for-size graft. GPx3 treatment delivered by hiPSC-MSCs could significantly ameliorated hepatic IR injury through inhibition of macrophages activation followed by decreased production of ROS, TNFα and IL-1.

II. The role of GPx3 in HCC. Down-regulation of GPx3 in liver tumor was observed in half of HCC patients (56/113). It significantly correlated with advanced pTNM stage (P = 0.024), presence of venous infiltration (P =0.043) and high AFP level (P = 0.006). The one year (P = 0.038) and five year (P = 0.019) recurrence rate were significantly higher in the patients with lower GPx3 expression. In functional study, rGPx3 administration and over-expression of GPx3 significantly suppressed proliferation and invasiveness of HCC cells in vitro and in vivo. The tumor suppressive activity of GPx3 was mediated by inhibition of EMT through Erk-NFκB-SIP1 pathway. The GPx3 treatment delivered by hiPSC-MSCs could significantly inhibit proliferation of MHCC97L.

Conclusions: I. Down-regulation of GPx3 was associated with small-for-size graft injury. Low circulating GPx3 at early phase after transplantation predicted higher tumor recurrence of HCC recipients. II. Down-regulation of GPx3 indicated poor prognosis of HCC patients. GPx3 suppressed tumor growth and invasiveness by inhibition of EMT through Erk-NFκB-SIP1 pathway. III. Engineered hiPSC-MSCs delivering GPx3 may possess therapeutic value in liver graft injury and HCC.