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

Abstract

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. Ó2016 AACR.

Meta-analysis of gene expression studies in endometrial cancer identifies gene expression profiles associated with aggressive disease and patient outcome

“…FBP1 plays a role in glucose metabolism and aerobic glycolysis, and has been reported to be downregulated in hepatocellular carcinoma, colorectal, breast, gastric, and renal cancer, reviewed in ref. 36. Downregulation of FBP1 is reported to contribute to tumor progression and poor survival of hepatocellular carcinoma36 and renal cell carcinoma patients37 and has been touted as a target for therapeutic interventions for these diseases.…”

“…36. Downregulation of FBP1 is reported to contribute to tumor progression and poor survival of hepatocellular carcinoma36 and renal cell carcinoma patients37 and has been touted as a target for therapeutic interventions for these diseases. Given the results for FBP1 expression in our study, it is conceivable that therapeutics developed targeting FBP1 may also be beneficial in the treatment of EEC.…”

Hidden features: exploring the non-canonical functions of metabolic enzymes

“…Mounting evidence suggests that FBP1 acts as a tumor suppressor in multiple cancer types (Chen et al, 2011; Dong et al, 2013; Hirata et al, 2016; Li et al, 2014). The transcriptional regulatory ability of FBP1 was first observed in clear cell renal cell carcinoma (ccRCC) tumors, in which FBP1 levels are uniformly decreased and FBP1 re-expression inhibits tumor progression by antagonizing glycolytic flux, thereby reducing the Warburg effect (Box 1) (Li et al, 2014).…”

Clinical significance of ZNF750 gene expression, a novel tumor suppressor gene, in esophageal squamous cell carcinoma

“…Written informed consent was obtained from all patients, and the Institutional Review Board of Kyushu University (Fukuoka, Japan) approved the present study. Sample collection was performed as previously described (13). Data on patient age, sex, histology, tumor depth of invasion, lymph node metastasis, lymphatic invasion, venous invasion and distant metastasis were obtained from the clinical and pathological records.…”