Increased expression of glycinamide ribonucleotide transformylase is associated with a poor prognosis in hepatocellular carcinoma, and it promotes liver cancer cell proliferation

SummaryGlycinamide ribonucleotide transformylase (GART) is a folate-dependent enzyme in the de novo purine pathway that has been the target of antineoplastic intervention for almost 2 decades. Until now, its expression and functional significance in hepatocellular carcinoma (HCC) have been unclear. We demonstrated by Western blotting that the expression of GART was markedly up-regulated in HCC patients. Immunohistochemistry staining was used to determine the expression of GART in HCC and adjacent nontumor tissues from 96 patients. Increased expression of GART correlated positively with the histologic grade (P = .001), tumor size (P = .043), number of tumorous nodes (P = .020), and intrahepatic metastases (P = .031), suggesting a role for GART in the progression of HCC. Patients with higher GART expression had a much worse overall survival rate than those with low expression (P = .002). Furthermore, multivariate analysis showed that GART expression was an independent predictor of overall survival (hazard ratio, 2.265; 95% confidence interval, 1.335-3.842; P = .002). Depletion of GART by small interfering RNA inhibited cell proliferation and blocked S-phase and mitotic entry in cultured HepG2 and BEL-7404 cells. Western blot analyses showed that GART depletion decreased the proliferating cell nuclear antigen concentration. Collectively, our clinical and in vitro data indicate that GART expression may be one of the causative factors for a poor prognosis in HCC.