title: Reactive oxygen species-mediated PKC and integrin signaling promotes tumor progression of human hepatoma HepG2.
abstract: The poor prognosis and recurrence of HCC are majorly caused by intrahepatic metastasis. Delineating the molecular pathways mediating these processes may benefit developing effective targeting therapies. Using human hepatoma HepG2 as a model, we have found reactive oxygen species (ROS) may cooperate with protein kinase C (PKC) for sustained ERK phosphorylation and migration of HepG2 induced by 12-O-tetradecanoyl-phorbol-13-acetate (TPA). We further investigated whether integrin signaling is involved. Various antagonists of integrin signaling prevented TPA-induced activation of ERK and PKC, ROS generation and migration of HepG2. On the other hand, TPA-induced phosphorylation of integrin signaling components including focal adhesion kinase (FAK), Src (Tyr416) and paxillin (Tyr31 and Ser178) can be prevented by PKC inhibitor Bisindolylmaleimides (BIS) and antioxidant dithiotheritol (DTT). HepG2 overexpressing PKCα contained elevated phosphorylated paxillin. Also, ROS generator phenazine methosulfate and tert-Butyl hydroperoxide may induce phosphorylation of paxillin and activation of PKC. Taken together, ROS mediated cross talk of PKC and integrin for migration of HepG2 induced by TPA. Furthermore, TPA induced intrahepatic metastasis of HepG2 in SCID mice, which was prevented by BIS or (BIS plus DTT). Elevated phosphorylation of paxillin was observed in tumor of mice treated with TPA as compared with those co-treated with TPA/BIS. In summary, the signal pathways for tumor progression of hepatoma induced by TPA can be established both in vitro and in vivo.
authors.affiliation: Research Centre for Hepatology, Department of Internal Medicine, Buddhist Tzu Chi General Hospital and Tzu Chi University, Hualein, Taiwan.
authors.forename: Chi-Tan
authors.initials: CT
authors.lastname: Hu
authors.forename: Jia-Ru
authors.initials: JR
authors.lastname: Wu
authors.forename: Chuan-Chu
authors.initials: CC
authors.lastname: Cheng
authors.forename: Sindy
authors.initials: S
authors.lastname: Wang
authors.forename: Hsiao-Ting
authors.initials: HT
authors.lastname: Wang
authors.forename: Ming-Che
authors.initials: MC
authors.lastname: Lee
authors.forename: Ling-Jung
authors.initials: LJ
authors.lastname: Wang
authors.forename: Siou-Mei
authors.initials: SM
authors.lastname: Pan
authors.forename: Tsu-Yao
authors.initials: TY
authors.lastname: Chang
authors.forename: Wen-Sheng
authors.initials: WS
authors.lastname: Wu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000556:secondary*; D002465:Cell Movement / Q000187:drug effects; D018450:Disease Progression; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D051571:Protein Kinase C-alpha / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D016023:Integrins; D017382:Reactive Oxygen Species; D051571:Protein Kinase C-alpha; D048049:Extracellular Signal-Regulated MAP Kinases; D013755:Tetradecanoylphorbol Acetate