| RRC ID |
64940
|
| 著者 |
Hirata H, Sugimachi K, Komatsu H, Ueda M, Masuda T, Uchi R, Sakimura S, Nambara S, Saito T, Shinden Y, Iguchi T, Eguchi H, Ito S, Terashima K, Sakamoto K, Hirakawa M, Honda H, Mimori K.
|
| タイトル |
Decreased Expression of Fructose-1,6-bisphosphatase Associates with Glucose Metabolism and Tumor Progression in Hepatocellular Carcinoma.
|
| ジャーナル |
Cancer Res
|
| 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. ©2016 AACR.
|
| 巻・号 |
76(11)
|
| ページ |
3265-76
|
| 公開日 |
2016-6-1
|
| DOI |
10.1158/0008-5472.CAN-15-2601
|
| PII |
0008-5472.CAN-15-2601
|
| PMID |
27197151
|
| MeSH |
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
RNA, Messenger / genetics
RNA-Binding Proteins
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Survival Rate
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
|
| IF |
9.727
|
| リソース情報 |
| ヒト・動物細胞 |
HuH-7(RCB1366)
Hep G2(RCB1886) |
