Growth arrest DNA damage-inducible gene 45 gamma expression as a prognostic and predictive biomarker in hepatocellular carcinoma
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Da-Liang Ou1,2, Song-Kun Shyue3, Liang-In Lin4, Zi-Rui Feng2,5, Jun-Yang Liou6, Hsiang-Hsuan Fan2,5, Bin-Shyun Lee2,5, Chiun Hsu1,5,7, Ann-Lii Cheng1,5,7,8
1Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan
2National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan
3Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
4Graduate Institute of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan
5Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
6Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan
7Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
8Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taiwan
Chiun Hsu, e-mail: [email protected]
Keywords: GADD45γ, hepatocellular carcinoma (HCC), sorafenib, CCAAT/enhancer binding protein (C/EBP), survivin
Received: February 26, 2015 Accepted: June 19, 2015 Published: June 29, 2015
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.
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