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Growth arrest DNA damage-inducible gene 45 gamma expression as a prognostic and predictive biomarker in hepatocellular carcinoma.
- Source :
-
Oncotarget [Oncotarget] 2015 Sep 29; Vol. 6 (29), pp. 27953-65. - Publication Year :
- 2015
-
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.
- Subjects :
- Aged
Animals
Antineoplastic Agents pharmacology
Apoptosis drug effects
Blotting, Western
CCAAT-Enhancer-Binding Proteins genetics
CCAAT-Enhancer-Binding Proteins metabolism
Carcinoma, Hepatocellular genetics
Carcinoma, Hepatocellular mortality
Cell Cycle Proteins analysis
Cell Cycle Proteins genetics
Cell Line, Tumor
Chromatin Immunoprecipitation
Female
Gene Expression Regulation, Neoplastic genetics
Humans
Kaplan-Meier Estimate
Liver Neoplasms genetics
Liver Neoplasms mortality
Male
Mice
Mice, Inbred BALB C
Middle Aged
Niacinamide analogs & derivatives
Niacinamide pharmacology
Nuclear Proteins analysis
Nuclear Proteins genetics
Phenylurea Compounds pharmacology
Prognosis
Proportional Hazards Models
RNA, Small Interfering
Reverse Transcriptase Polymerase Chain Reaction
Sorafenib
Transfection
Xenograft Model Antitumor Assays
Biomarkers, Tumor analysis
Carcinoma, Hepatocellular pathology
Cell Cycle Proteins biosynthesis
Drug Resistance, Neoplasm genetics
Liver Neoplasms pathology
Nuclear Proteins biosynthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1949-2553
- Volume :
- 6
- Issue :
- 29
- Database :
- MEDLINE
- Journal :
- Oncotarget
- Publication Type :
- Academic Journal
- Accession number :
- 26172295
- Full Text :
- https://doi.org/10.18632/oncotarget.4446