Glutathione peroxidase 3 (GPx3) suppressed HCC invasiveness through JNK-cJun-MMP2 signaling pathway - Application of in vivo real-time molecular imaging

Abstract

OBJECTIVE: Our recent study [1] showed that GPx3 possessed prognostic and therapeutic value in HCC. With the latest development of in vivo imaging modality, it allows us to kinetically observe the process of tumor invasion in a microview and directly see the cells in a living animal. We here intended to explore the suppressive role of GPx3 in HCC invasiveness using in vivo imaging platform. METHODS: The correlation of GPx3 expression with tumor recurrence was investigated in a rat orthotopic liver transplantation model and further validated in clinical samples from 106 HCC recipients. The ectopic liver cancer model with dorsal window chamber was established to kinetically observe the effect of GPx3 on tumor invasion using in vivo imaging system. The suppressive effect of GPx3 on lung metastasis was also investigated. The mechanism was further explored. RESULTS: GPx3 was significantly down-regulated (day1: 33 vs 1147; day3: 3209 vs 4459; day7: 303 vs 2506; mU/mL, P<0.05) in the rat with small-for-size graft, which provided favourable micro-environment for tumor recurrence. Consistently, lower plasma GPx3 significantly correlated with more tumor recurrence of HCC patients post-transplantation (day1: 4.16 vs 8.99 μg/mL; day7: 3.86 vs 9.99 μg/mL; P<0.01). The lower plasma GPx3 indicated poor overall and disease-free survival outcome. The in vitro study showed that over-expression of GPx3 significantly inhibited wound healing and Matrigel invasion of HCC cells. The in vivo imaging showed that over-expression of GPx3 significantly suppressed the capacity of HCC cells invading into surrounding connective tissues at different time points after tumor established.