title: Hydrogen peroxide inducible clone-5 mediates reactive oxygen species signaling for hepatocellular carcinoma progression.
abstract: One of the signaling components involved in hepatocellular carcinoma (HCC) progression is the focal adhesion adaptor paxillin. Hydrogen peroxide inducible clone-5 (Hic-5), one of the paralogs of paxillin, exhibits many biological functions distinct from paxillin, but may cooperate with paxillin to trigger tumor progression. Screening of Hic-5 in 145 surgical HCCs demonstrated overexpression of Hic-5 correlated well with intra- and extra-hepatic metastasis. Hic-5 highly expressed in the patient derived HCCs with high motility such as HCC329 and HCC353 but not in the HCCs with low motility such as HCC340. Blockade of Hic-5 expression prevented constitutive migration of HCC329 and HCC353 and HGF-induced cell migration of HCC340. HCC329Hic-5(-), HCC353Hic-5(-), HCC372Hic-5(-), the HCCs stably depleted of Hic-5, exhibited reduced motility compared with each HCC expressing Scramble shRNA. Moreover, intra/extrahepatic metastasis of HCC329Hic-5(-) in SCID mice greatly decreased compared with HCC329Scramble. On the other hand, ectopic Hic-5 expression in HCC340 promoted its progression. Constitutive and HGF-induced Hic-5 expression in HCCs were suppressed by the reactive oxygen species (ROS) scavengers catalase and dithiotheritol and c-Jun N-terminal kinase (JNK) inhibitor SP600125. On the contrary, depletion of Hic-5 blocked constitutive and HGF-induced ROS generation and JNK phosphorylation in HCCs. Also, ectopic expression of Hic-5 enhanced ROS generation and JNK phosphorylation. These highlighted that Hic-5 plays a central role in the positive feedback ROS-JNK signal cascade. Finally, the Chinese herbal derived anti-HCC peptide LZ-8 suppressed constitutive Hic-5 expression and JNK phosphorylation. In conclusion, Hic-5 mediates ROS-JNK signaling and may serve as a therapeutic target for prevention of HCC progression.
authors.affiliation: Institute of Medical Sciences, College of Medicine, Tzu Chi University, Hualien, Taiwan.
authors.forename: Jia-Ru
authors.initials: JR
authors.lastname: Wu
authors.affiliation: Research Centre for Hepatology, Department of Internal Medicine, Buddhist Tzu Chi General Hospital and Tzu Chi University, Hualien, Taiwan.
authors.forename: Chi-Tan
authors.initials: CT
authors.lastname: Hu
authors.affiliation: Department of Laboratory Medicine and Biotechnology, College of Medicine, Tzu Chi University, Hualien, Taiwan.
authors.forename: Ren-In
authors.initials: RI
authors.lastname: You
authors.affiliation: Research Centre for Hepatology, Department of Internal Medicine, Buddhist Tzu Chi General Hospital and Tzu Chi University, Hualien, Taiwan.
authors.forename: Siou-Mei
authors.initials: SM
authors.lastname: Pan
authors.affiliation: Department of Laboratory Medicine and Biotechnology, College of Medicine, Tzu Chi University, Hualien, Taiwan.
authors.forename: Chuan-Chu
authors.initials: CC
authors.lastname: Cheng
authors.affiliation: Department of Surgery, Buddhist Tzu Chi General Hospital, School of Medicine, Tzu Chi University, Hualien, Taiwan.
authors.forename: Ming-Che
authors.initials: MC
authors.lastname: Lee
authors.affiliation: Department of Surgery, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, School of Medicine, Tzu Chi University, Hualien, Taiwan.
authors.forename: Chao-Chuan
authors.initials: CC
authors.lastname: Wu
authors.affiliation: Department of Surgery, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, School of Medicine, Tzu Chi University, Hualien, Taiwan.
authors.forename: Yao-Jen
authors.initials: YJ
authors.lastname: Chang
authors.affiliation: Research Centre for Hepatology, Department of Internal Medicine, Buddhist Tzu Chi General Hospital and Tzu Chi University, Hualien, Taiwan.
authors.forename: Shu-Chuan
authors.initials: SC
authors.lastname: Lin
authors.affiliation: Department of Laboratory Medicine and Biotechnology, College of Medicine, Tzu Chi University, Hualien, Taiwan.
authors.forename: Chang-Shan
authors.initials: CS
authors.lastname: Chen
authors.affiliation: Department of Laboratory Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.
authors.forename: Teng-Yi
authors.initials: TY
authors.lastname: Lin
authors.affiliation: Department of Laboratory Medicine and Biotechnology, College of Medicine, Tzu Chi University, Hualien, Taiwan.
authors.forename: Wen-Sheng
authors.initials: WS
authors.lastname: Wu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D002465:Cell Movement; D018450:Disease Progression; D004789:Enzyme Activation; D005656:Fungal Proteins / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D060588:LIM Domain Proteins / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D005656:Fungal Proteins; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; C490351:TGFB1I1 protein, human; C061148:LZ-8 protein, Ganoderma lucidum; D048031:JNK Mitogen-Activated Protein Kinases
keywords: HGF; JNK; metastasis; migration; paxillin