Growth arrest dna damage-inducible gene 45 gamma expression as a prognostic and predictive biomarker in hepatocellular carcinoma
Journal
Oncotarget
Journal Volume
6
Journal Issue
29
Pages
27953-27965
Date Issued
2015
Author(s)
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 GADD45? in hepatocellular carcinoma (HCC) treatment. GADD45? expression in HCC cells was examined using quantitative reverse transcription-PCR (qRT-PCR) and Western blotting. The control of GADD45? transcription was examined using a luciferase reporter assay and chromatin immunoprecipitation. The in vivo induction of GADD45? was performed using adenoviral transfer. The expression of GADD45? in HCC tumor tissues from patients who had undergone curative resection was measured using qRT-PCR. Sorafenib induced expression of GADD45? mRNA and protein, independent of its RAF kinase inhibitor activity. GADD45? 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 GADD45? reversed sorafenib resistance in vitro and in vivo, whereas GADD45? 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 GADD45? overexpression and sorafenib treatment, suggesting that survivin is a crucial mediator of antitumor effects of GADD45?. GADD45? expression decreased in tumors from patients with HCC who had undergone curative surgery, and low GADD45? expression was an independent prognostic factor for poor survival, in addition to old age and vascular invasion. The preceding data indicate that GADD45? suppression is a poor prognostic factor in patients with HCC and may help predict sorafenib efficacy in HCC.
SDGs
Other Subjects
CCAAT enhancer binding protein; CCAAT enhancer binding protein epsilon; death receptor 5; Fas associated death domain protein; growth arrest and DNA damage inducible protein 45; messenger RNA; protein mcl 1; small interfering RNA; sorafenib; survivin; antineoplastic agent; carbanilamide derivative; CCAAT enhancer binding protein; cell cycle protein; GADD45A protein, human; nicotinamide; nuclear protein; sorafenib; tumor marker; adult; aged; animal experiment; animal model; animal tissue; apoptosis; Article; cancer inhibition; cancer prognosis; cancer resistance; cancer surgery; cancer survival; chromatin immunoprecipitation; clinical article; controlled study; drug efficacy; female; GADD45 gene; gene expression regulation; gene overexpression; gene silencing; human; human cell; human tissue; in vitro study; in vivo study; liver cell carcinoma; luciferase assay; lymph vessel metastasis; male; mouse; nonhuman; outcome assessment; overall survival; predictive value; protein expression; protein function; reverse transcription polymerase chain reaction; survival prediction; survival time; transcription regulation; tumor xenograft; Western blotting; analogs and derivatives; animal; Bagg albino mouse; biosynthesis; drug effects; drug resistance; drug screening; genetic transfection; genetics; Kaplan Meier method; liver cell carcinoma; liver tumor; metabolism; middle aged; mortality; pathology; prognosis; proportional hazards model; tumor cell line; Aged; Animals; Antineoplastic Agents; Apoptosis; Biomarkers, Tumor; Blotting, Western; Carcinoma, Hepatocellular; CCAAT-Enhancer-Binding Proteins; Cell Cycle Proteins; Cell Line, Tumor; Chromatin Immunoprecipitation; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Humans; Kaplan-Meier Estimate; Liver Neoplasms; Male; Mice; Mice, Inbred BALB C; Middle Aged; Niacinamide; Nuclear Proteins; Phenylurea Compounds; Prognosis; Proportional Hazards Models; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering; Transfection; Xenograft Model Antitumor Assays
Type
journal article