title: Emerging role of autophagy during ischemia-hypoxia and reperfusion in             hepatocellular carcinoma.
abstract: Hepatocellular carcinoma (HCC) is the most common primary malignancy found in the liver. Autophagy is the intracellular bulk degradation process for long-lived proteins and dysfunctional organelles. In this study, we report that autophagy plays a role in HCC cell proliferation in response to ischemia-hypoxia (I/H) and reperfusion and discuss its potential therapeutic implications. By establishing a simulated model in cultured HepG2 (p53 wild-type) and Hep3B (p53 null) hepatoma cells in vitro, we found that exposure to I/H induced a significant increase in microtubule-associated protein 1 light chain 3 (LC3) lipidation and subsequent LC3 puncta formation. While the proliferation of HCC cells was stimulated upon acute I/H exposure compared to that of control, inhibition of autophagy by autophagy-related protein 7 interference abolished it. In addition, the steady-state levels of sequestosome 1 (p62) in both HepG2 and Hep3B cells were reduced following I/H exposure, supporting the notion that acute I/H induces autophagy. Intriguingly, the p62 level further decreased during reperfusion following I/H, accompanied by increased LC3 lipidation. The intracellular reactive oxygen species (ROS) accumulated during acute I/H exposure and persisted through reperfusion in both HepG2 and Hep3B cells and the ROS levels increased at a much faster rate during reperfusion than during I/H periods in both cells. Autophagy functions as a promoter for HCC cell survival during acute I/H and reperfusion and this also points to potential therapy for hepatoma by perturbing the acute I/H-reperfusion-autophagy axis.
authors.affiliation: Department of Thoracic Surgery, Ruijin Hospital, Shanghai Jiao                     Tong University School of Medicine, Shanghai 200025, P.R. China.
authors.forename: Hailei
authors.initials: H
authors.lastname: Du
authors.forename: Weiping
authors.initials: W
authors.lastname: Yang
authors.forename: Lin
authors.initials: L
authors.lastname: Chen
authors.forename: Baiyong
authors.initials: B
authors.lastname: Shen
authors.forename: Chenghong
authors.initials: C
authors.lastname: Peng
authors.forename: Hongwei
authors.initials: H
authors.lastname: Li
authors.forename: David K
authors.initials: DK
authors.lastname: Ann
authors.forename: Yun
authors.initials: Y
authors.lastname: Yen
authors.forename: Weihua
authors.initials: W
authors.lastname: Qiu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D001343:Autophagy; D000071193:Autophagy-Related Protein 7; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000378:metabolism*; D015687:Cell Hypoxia; D049109:Cell Proliferation; D002470:Cell Survival; D056945:Hep G2 Cells; D006801:Humans; D007511:Ischemia; D008113:Liver Neoplasms / Q000098:blood supply / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015424:Reperfusion; D000071456:Sequestosome-1 Protein; D044764:Ubiquitin-Activating Enzymes / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D017382:Reactive Oxygen Species; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes