title: The Clinical Significance and Potential Therapeutic Role of GPx3 in Tumor Recurrence after Liver Transplantation.
abstract: Our previous study showed that small-for-size liver graft may provide favorable micro-environment for tumor growth. GPx3, an anti-oxidant, not only attenuates oxidative stress, but also suppresses liver tumor growth in our recent study. Here, we aimed to characterize the clinical significance and explore the functional role of GPx3 in HCC recurrence after liver transplantation.
  
  
  
  To explore the association between GPx3 expression and HCC invasiveness, a rat orthotopic liver transplantation model with tumor development was established. To investigate the clinical relevance of GPx3, 105 HCC patients who underwent liver transplantation were recruited. The suppressive role of GPx3 in HCC cells was studied using wound healing, Matrigel invasion assay and lung metastasis model. The real-time intravital imaging system was applied to directly visualize the tumor cells invasion in a living animal. The underlying mechanism was further explored.
  
  
  
  GPx3 was identified as a down-regulated protein in small-for-size liver graft and significantly associated with invasive phenotype of tumor growth in a rat model. Plasma GPx3 was significantly lower in small-for-size graft group post-transplantation (day1: 33 vs 1147; day3: 3209 vs 4459; day7: 303 vs 2506; mU/mL, P<0.05) in rat model. Clinically, the plasma GPx3 was significantly lower in the recipients with HCC recurrence post-transplantation (day1: 4.16 vs 8.99 µg/mL, P<0.001; day7: 3.86 vs 9.99 µg/mL, P<0.001). Furthermore, lower plasma GPx3 was identified as an independent predictor (HR=4.528, P=0.046) for poor overall survival post-transplantation. Over-expression of GPx3 significantly suppressed migration, invasiveness and metastasis of HCC cells. Real-time intravital imaging showed that GPx3 significantly suppressed HCC invasiveness in a live animal. GPx3 suppressed the tumor invasiveness through inhibition of JNK-cJun-MMP2 pathway.
  
  
  
  GPx3 may possess prognostic and therapeutic value for HCC patients after liver transplantation.
authors: Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong.
authors: Xiang
authors: X
authors: Qi
authors: Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong.
authors: Kevin Tak-Pan
authors: KT
authors: Ng
authors: Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong.
authors: Yan
authors: Y
authors: Shao
authors: Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong.
authors: Chang Xian
authors: CX
authors: Li
authors: Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong.
authors: Wei
authors: W
authors: Geng
authors: Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong.
authors: Chang Chun
authors: CC
authors: Ling
authors: Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong.
authors: Yuen Yuen
authors: YY
authors: Ma
authors: Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong.
authors: Xiao Bing
authors: XB
authors: Liu
authors: Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong.
authors: Hui
authors: H
authors: Liu
authors: Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong.
authors: Jiang
authors: J
authors: Liu
authors: Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong.
authors: Wai Ho
authors: WH
authors: Yeung
authors: Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong.; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, China.
authors: Chung Mau
authors: CM
authors: Lo
authors: Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong.; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, China.
authors: Kwan
authors: K
authors: Man
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis* / Q000473:pathology / Q000628:therapy; D005979:Glutathione Peroxidase / Q000008:administration & dosage* / Q000097:blood*; D006801:Humans; D008113:Liver Neoplasms / Q000175:diagnosis* / Q000517:prevention & control*; D016031:Liver Transplantation; D008819:Mice, Nude; D011379:Prognosis; D051381:Rats; D055502:Secondary Prevention
chemical_list: D000970:Antineoplastic Agents; C486484:GPX3 protein, human; C505355:GPX3 protein, rat; D005979:Glutathione Peroxidase
keywords: GPx3; HCC invasiveness; intravital imaging; liver transplantation.