TY - JOUR
T1 - Decreased expression of fructose-1,6-bisphosphatase associates with glucose metabolism and tumor progression in hepatocellular carcinoma
AU - Hirata, Hidenari
AU - Sugimachi, Keishi
AU - Komatsu, Hisateru
AU - Ueda, Masami
AU - Masuda, Takaaki
AU - Uchi, Ryutaro
AU - Sakimura, Shotaro
AU - Nambara, Sho
AU - Saito, Tomoko
AU - Shinden, Yoshiaki
AU - Iguchi, Tomohiro
AU - Eguchi, Hidetoshi
AU - Ito, Shuhei
AU - Terashima, Kotaro
AU - Sakamoto, Katsumi
AU - Hirakawa, Masakazu
AU - Honda, Hiroshi
AU - Mimori, Koshi
N1 - Funding Information:
This research used the supercomputing resource provided by the Human Genome Center, Institute of Medical Science, the University of Tokyo (http://sc.hgc.jp/shirokane.html). The authors thank Dr. A. Niida for providing bioinformatics tools, K. Oda, M. Kasagi, T. Kawano, and J. Takano for technical assistance, Hiroshima Red Cross Hospital, Iizuka Hospital, and Oita Red Cross Hospital for providing clinical samples. The authors also appreciate the technical assistance from The Research Support Center, Research Center for Human Disease Modeling, Kyushu University. This work was supported in part by the Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research (grant numbers 24592005, 26861003, 15K10168, and 15H04921). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
©2016 AACR.
PY - 2016/6/1
Y1 - 2016/6/1
N2 - 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 over-expression 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.
AB - 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 over-expression 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.
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U2 - 10.1158/0008-5472.CAN-15-2601
DO - 10.1158/0008-5472.CAN-15-2601
M3 - Article
C2 - 27197151
AN - SCOPUS:84975038089
VL - 76
SP - 3265
EP - 3276
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 11
ER -