title: Growth arrest DNA damage-inducible gene 45 gamma expression as a prognostic and predictive biomarker in hepatocellular carcinoma.
abstract: Growth arrest DNA damage-inducible gene 45 (GADD45) family proteins play a crucial role in regulating cellular stress responses and apoptosis. The present study explored the prognostic and predictive role of GADD45γ in hepatocellular carcinoma (HCC) treatment. GADD45γ expression in HCC cells was examined using quantitative reverse transcription-PCR (qRT-PCR) and Western blotting. The control of GADD45γ transcription was examined using a luciferase reporter assay and chromatin immunoprecipitation. The in vivo induction of GADD45γ was performed using adenoviral transfer. The expression of GADD45γ in HCC tumor tissues from patients who had undergone curative resection was measured using qRT-PCR. Sorafenib induced expression of GADD45γ mRNA and protein, independent of its RAF kinase inhibitor activity. GADD45γ induction was more prominent in sorafenib-sensitive HCC cells (Huh-7 and HepG2, IC50 6-7 μM) than in sorafenib-resistant HCC cells (Hep3B, Huh-7R, and HepG2R, IC50 12-15 μM). Overexpression of GADD45γ reversed sorafenib resistance in vitro and in vivo, whereas GADD45γ expression knockdown by using siRNA partially abrogated the proapoptotic effects of sorafenib on sorafenib-sensitive cells. Overexpression of survivin in HCC cells abolished the antitumor enhancement between GADD45γ overexpression and sorafenib treatment, suggesting that survivin is a crucial mediator of antitumor effects of GADD45γ. GADD45γ expression decreased in tumors from patients with HCC who had undergone curative surgery, and low GADD45γ expression was an independent prognostic factor for poor survival, in addition to old age and vascular invasion. The preceding data indicate that GADD45γ suppression is a poor prognostic factor in patients with HCC and may help predict sorafenib efficacy in HCC.
authors.affiliation: Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan.|National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Da-Liang
authors.initials: DL
authors.lastname: Ou
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Song-Kun
authors.initials: SK
authors.lastname: Shyue
authors.affiliation: Graduate Institute of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Liang-In
authors.initials: LI
authors.lastname: Lin
authors.affiliation: National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan.|Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Zi-Rui
authors.initials: ZR
authors.lastname: Feng
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Jun-Yang
authors.initials: JY
authors.lastname: Liou
authors.affiliation: National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan.|Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Hsiang-Hsuan
authors.initials: HH
authors.lastname: Fan
authors.affiliation: National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan.|Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Bin-Shyun
authors.initials: BS
authors.lastname: Lee
authors.affiliation: Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan.|Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.|Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Chiun
authors.initials: C
authors.lastname: Hsu
authors.affiliation: Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan.|Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.|Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.|Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Ann-Lii
authors.initials: AL
authors.lastname: Cheng
mesh_terms: D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000032:analysis*; D015153:Blotting, Western; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D018797:Cell Cycle Proteins / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D009687:Nuclear Proteins / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D010671:Phenylurea Compounds / Q000494:pharmacology; D011379:Prognosis; D016016:Proportional Hazards Models; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077157:Sorafenib; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D000097642:GADD45 Proteins
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D022762:CCAAT-Enhancer-Binding Proteins; D018797:Cell Cycle Proteins; D009536:Niacinamide; D009687:Nuclear Proteins; D010671:Phenylurea Compounds; D034741:RNA, Small Interfering; D000077157:Sorafenib; C439070:GADD45A protein, human; D000097642:GADD45 Proteins
keywords: CCAAT/enhancer binding protein (C/EBP); GADD45γ; hepatocellular carcinoma (HCC); sorafenib; survivin