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 GADD45gamma in hepatocellular carcinoma (HCC) treatment. GADD45gamma expression in HCC cells was examined using quantitative reverse transcription-PCR (qRT-PCR) and Western blotting. The control of GADD45gamma transcription was examined using a luciferase reporter assay and chromatin immunoprecipitation. The in vivo induction of GADD45gamma was performed using adenoviral transfer. The expression of GADD45gamma in HCC tumor tissues from patients who had undergone curative resection was measured using qRT-PCR. Sorafenib induced expression of GADD45gamma mRNA and protein, independent of its RAF kinase inhibitor activity. GADD45gamma induction was more prominent in sorafenib-sensitive HCC cells (Huh-7 and HepG2, IC50 6-7 muM) than in sorafenib-resistant HCC cells (Hep3B, Huh-7R, and HepG2R, IC50 12-15 muM). Overexpression of GADD45gamma reversed sorafenib resistance in vitro and in vivo, whereas GADD45gamma 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 GADD45gamma overexpression and sorafenib treatment, suggesting that survivin is a crucial mediator of antitumor effects of GADD45gamma. GADD45gamma expression decreased in tumors from patients with HCC who had undergone curative surgery, and low GADD45gamma expression was an independent prognostic factor for poor survival, in addition to old age and vascular invasion. The preceding data indicate that GADD45gamma suppression is a poor prognostic factor in patients with HCC and may help predict sorafenib efficacy in HCC.
