Clinical significance and therapeutic value of glutathione peroxidase 3 (GPx3) in hepatocellular carcinoma

// Xiang Qi 1 , Kevin Tak Pan Ng 1 , Qi Zhou Lian 2 , Xiao Bing Liu 1 , Chang Xian Li 1 , Wei Geng 1 , Chang Chun Ling 1 , Yuen Yuen Ma 1 , Wai Ho Yeung 1 , Wen Wei Tu 3 , Sheung Tat Fan 1 , Chung Mau Lo 1 , Kwan Man 1 1 Department of Surgery, Centre for Cancer Research, The University of Hong Kong, Pokfulam, Hong Kong, China. 2 Department of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China. 3 Department of Paediatrics & Adolescent Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China. Correspondence to: Kwan Man, e-mail: kwanman@hku.hk Keywords: GPx3, HCC, hiPSC-MSCs, Tumor suppressor gene, Prognosis Received: July 24, 2014 Accepted: September 30, 2014 Published: October 11, 2014 ABSTRACT Aims: We aimed to investigate the clinical significance of GPx3 in hepatocellular carcinoma (HCC) and to characterize its tumor suppressive role. Methods: HCC patients (113) who underwent hepatectomy were recruited to examine the clinical relevance of GPx3. The tumor suppressive role of GPx3 was studied by administration of recombinant GPx3 (rGPx3) or over-expression of GPx3 in HCC cells in vitro and in vivo . The therapeutic value of GPx3 for HCC was further investigated using human induced pluripotent stem cell derived mesenchymal stem cells (hiPSC-MSCs) as its delivery vehicle. Results: Down-regulation of GPx3 significantly correlated with advanced tumor stage ( P = 0.024), venous infiltration ( P = 0.043) and poor overall survival ( P = 0.007) after hepatectomy. Lower plasma GPx3 in HCC patients was significantly associated with larger tumor size ( P = 0.011), more tumor nodules ( P = 0.032) and higher recurrence ( P = 0.016). Over-expression of GPx3 or administration of rGPx3 significantly inhibited proliferation and invasiveness of HCC cells in vitro and in vivo . Tumor suppressive activity of GPx3 was mediated through Erk-NFκB-SIP1 pathway. GPx3 could be delivered by hiPSC-MSCs into the tumor and exhibited tumor suppressive activity in vivo . Conclusions: GPx3 is a tumor suppressor gene in HCC and may possess prognostic and therapeutic value for HCC patients.