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

• Published in: Oncotarget Vol. 5; no. 22; pp. 11103 - 11120
• Main Authors: Qi, Xiang, Ng, Kevin Tak Pan, Lian, Qi Zhou, Liu, Xiao Bing, Li, Chang Xian, Geng, Wei, Ling, Chang Chun, Ma, Yuen Yuen, Yeung, Wai Ho, Tu, Wen Wei, Fan, Sheung Tat, Lo, Chung Mau, Man, Kwan
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 30.11.2014
• Subjects: Adult; Aged; Aged, 80 and over; Animals; Biomarkers, Tumor - metabolism; Carcinoma, Hepatocellular - enzymology; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Carcinoma, Hepatocellular - therapy; Cell Line, Tumor; Cell Proliferation - physiology; Clinical Research Paper; Down-Regulation; Female; Genes, Tumor Suppressor; Glutathione Peroxidase - administration & dosage; Glutathione Peroxidase - biosynthesis; Glutathione Peroxidase - genetics; Glutathione Peroxidase - metabolism; Humans; Liver Neoplasms - enzymology; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Liver Neoplasms - therapy; Male; Mesenchymal Stem Cell Transplantation - methods; Mesenchymal Stromal Cells - enzymology; Mice; Mice, Nude; Middle Aged; Oxidative Stress - drug effects; Oxidative Stress - physiology; Pluripotent Stem Cells - enzymology; Prognosis; Recombinant Proteins - pharmacology; Xenograft Model Antitumor Assays; Young Adult
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.2549

We aimed to investigate the clinical significance of GPx3 in hepatocellular carcinoma (HCC) and to characterize its tumor suppressive role. 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. 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. GPx3 is a tumor suppressor gene in HCC and may possess prognostic and therapeutic value for HCC patients.