Decreased Expression of Fructose-1,6-bisphosphatase Associates with Glucose Metabolism and Tumor Progression in Hepatocellular Carcinoma

• Published in: Cancer research (Chicago, Ill.) Ill.), 2016-06, Vol.76 (11), p.3265-3276
• Main Authors: Hirata, Hidenari, Sugimachi, Keishi, Komatsu, Hisateru, Ueda, Masami, Masuda, Takaaki, Uchi, Ryutaro, Sakimura, Shotaro, Nambara, Sho, Saito, Tomoko, Shinden, Yoshiaki, Iguchi, Tomohiro, Eguchi, Hidetoshi, Ito, Shuhei, Terashima, Kotaro, Sakamoto, Katsumi, Hirakawa, Masakazu, Honda, Hiroshi, Mimori, Koshi
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Blotting, Western; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Case-Control Studies; Cell Proliferation; DNA Helicases - genetics; DNA Helicases - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Female; Follow-Up Studies; Gene Expression Regulation, Neoplastic; Gluconeogenesis - physiology; Glucose - metabolism; Humans; Immunoenzyme Techniques; Liver - metabolism; Liver - pathology; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Recurrence, Local - genetics; Neoplasm Recurrence, Local - metabolism; Neoplasm Recurrence, Local - pathology; Neoplasm Staging; Prognosis; Promoter Regions, Genetic - genetics; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Survival Rate; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-15-2601

Fructose-1,6-bisphosphatase (FBP1), the rate-limiting enzyme in gluconeogenesis, is reduced in expression in certain cancers where it has been hypothesized to act as a tumor suppressor, including in hepatocellular carcinoma (HCC). Here, we report functional evidence supporting this hypothesis, providing a preclinical rationale to develop FBP1 as a therapeutic target for HCC treatment. Three independent cohorts totaling 594 cases of HCC were analyzed to address clinical significance. Lower FBP1 expression associated with advanced tumor stage, poor overall survival, and higher tumor recurrence rates. In HCC cell lines, where endogenous FBP1 expression is low, engineering its ectopic overexpression inhibited tumor growth and intracellular glucose uptake by reducing aerobic glycolysis. In patient specimens, promoter methylation and copy-number loss of FBP1 were independently associated with decreased FBP1 expression. Similarly, FBP1 downregulation in HCC cell lines was also associated with copy-number loss. HCC specimens exhibiting low expression of FBP1 had a highly malignant phenotype, including large tumor size, poor differentiation, impaired gluconeogenesis, and enhanced aerobic glycolysis. The effects of FBP1 expression on prognosis and glucose metabolism were confirmed by gene set enrichment analysis. Overall, our findings established that FBP1 downregulation in HCC contributed to tumor progression and poor prognosis by altering glucose metabolism, and they rationalize further study of FBP1 as a prognostic biomarker and therapeutic target in HCC patients. Cancer Res; 76(11); 3265-76. ©2016 AACR.