Assessment of Glut-1 expression in cholangiocarcinoma, benign biliary lesions and hepatocellular carcinoma

Zimmerman, R. L.; Fogt, Franz; Burke, Melissa; Murakata, Linda A.

doi:10.3892/or.9.4.689

Oncol Rep

2002

DOI: 10.3892/or.9.4.689

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Assessment of Glut-1 expression in cholangiocarcinoma, benign biliary lesions and hepatocellular carcinoma

R. L. Zimmerman

Franz Fogt²,

Melissa Burke³

et al.

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Cited by 22 publications

(44 citation statements)

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“…Those poorly differentiated HCCs show high uptake of 18 F-FDG on the 18 F-FDG PET scan and poor survival (2,3). Therefore, HKII appears to play an important role in maintaining malignancy in tumor cells with poor survival, but molecular mechanisms, especially the relationship between 18 F-FDG uptake mechanisms with regard to tumor progression, have not yet been well investigated.…”

mentioning

confidence: 99%

“…V-akt murine thymoma viral oncogene (Akt), known as a protein kinase B, mediates translocation of cytosolic HKII to the mitochondrial outer membrane for producing a VDAC-ANT-HKII complex that prevents cytochrome c release and apoptosis. From the clinical aspect, poorly differentiated HCC expresses HKII much higher than low-grade HCC, although Glut-1 expression is not always increased (5,17,18). Those poorly differentiated HCCs show high uptake of 18 F-FDG on the 18 F-FDG PET scan and poor survival (2,3).…”

mentioning

confidence: 99%

“…Because of its high sensitivity and specificity in the diagnosis and staging of various cancers or detection of recurrent tumors after treatment, 18 F-FDG PET is widely used in the oncology field (1). As cancer cell growth depends on glucose metabolism as a major energy substrate, increased 18 F-FDG uptake on PET scans is known to be an indicator of the poor prognosis and aggressiveness of various tumors (2,3).…”

mentioning

confidence: 99%

“…The main mechanisms of 18 F-FDG uptake in tumor cells are increased expression of the facilitated glucose transporters including type 1 (Glut-1) on the cell membrane and rate-limiting glycolytic enzymes, especially hexokinase type II (HKII) (4). It has been reported that well-differentiated hepatocellular carcinoma (HCC) shows low 18 F-FDG uptake, but poorly differentiated HCC shows increased HKII expression and, subsequently, increased 18 F-FDG uptake (5).…”

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confidence: 99%

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Evaluation of the Role of Hexokinase Type II in Cellular Proliferation and Apoptosis Using Human Hepatocellular Carcinoma Cell Lines

Ahn

Hwang²,

Park³

et al. 2009

J Nucl Med

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The 18 F-FDG uptake pattern on PET could be an indicator of the prognosis and aggressiveness of various tumors, including hepatocellular carcinoma (HCC). Hexokinase, especially hexokinase type II (HKII), plays a critical role in 18 F-FDG uptake in rapidly growing tumors. We established a stable cell line overexpressing HKII by the transfection of full DNA of HKII to HCC cells (SNU449) that express low levels of HKII and investigated how 18 F-FDG uptake mechanisms, especially overexpression of HKII, are linked to tumor proliferation mechanisms. Methods: The HKII gene was stably transfected to SNU449 cells with an expression vector. HKII expression in the cells was verified by reverse-transcriptase polymerase chain reaction, Western blot analysis, adenosine triphosphate (ATP) and lactate production, 18 F-FDG uptake measurement, and confocal microscopy. Cellular proliferation activity and response to the anticancer drug cisplatin were evaluated by cell counting using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. For the evaluation of molecular pathways involved in tumor proliferation, the phosphatidylinositol 3-kinase (PI3K)/Akt pathway was investigated. Results: The stable cell line produced HKII effectively, but expression of other enzymes or transporters for glycolysis, such as glucose-6-phosphatase (G6Pase), HKI and III, and glucose transporter type 1 and 2 (Glut-1 and Glut-2), did not show any changes. 18 F-FDG uptake was significantly increased after transfection. ATP and lactate production was also increased after transfection. Overexpressed HKII was associated with mitochondria on confocal microscopy. Cells with overexpression of HKII, compared with the nontransfected cell line, showed 1.5-to 2-fold higher cell survival and resistance to the anticancer agent cisplatin (2-to 8-fold). In the molecular study, the activated form of Akt was increased after transfection, and PI3K inhibitor dissociated the mitochondrial HKII to the cytoplasm. In addition, the adenosine monophosphate-activated protein kinase (AMPK) pathway is also involved in Akt signaling. Conclusion: HKII plays an important role in 18 F-FDG uptake and tumor proliferation by both the PI3K-dependent and the PI3K-independent Akt signal pathways; therefore, the 18 F-FDG uptake pattern on a PET scan can be a surrogate marker of prognosis in HCC.

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mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Evaluation of the Role of Hexokinase Type II in Cellular Proliferation and Apoptosis Using Human Hepatocellular Carcinoma Cell Lines

Ahn

Hwang²,

Park³

et al. 2009

J Nucl Med

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“…11,12 Studies regarding GLUT1 expression in HCC have revealed inconclusive results, and the biological significance of GLUT1 expression in HCC remains unknown. [13][14][15][16][17][18][19] Here, we show that GLUT1 expression is increased in a significant number of HCC cell lines and tissues, and high GLUT1 expression correlates with HCC proliferation and invasiveness. Furthermore, we found that siRNA-mediated abrogation of GLUT1 in HCC cell lines inhibits their proliferative and migratory potential.…”

mentioning

confidence: 99%

GLUT1 Expression Is Increased in Hepatocellular Carcinoma and Promotes Tumorigenesis

Amann

Maegdefrau

Hartmann

et al. 2009

The American Journal of Pathology

291

217

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Accelerated glycolysis is one of the biochemical characteristics of cancer cells. The glucose transporter isoform 1 (GLUT1) gene encodes a key rate-limiting factor in glucose transport into cancer cells. However, its expression level and functional significance in hepatocellular cancer (HCC) are still disputed. Therefore, we aimed to analyze the expression and function of the GLUT1 gene in cases of HCC. We found significantly higher GLUT1 mRNA expression levels in HCC tissues and cell lines compared with primary human hepatocytes and matched nontumor tissue. Immunohistochemical analysis of a tissue microarray of 152 HCC cases revealed a significant correlation between Glut1 protein expression levels and a higher Ki-67 labeling index, advanced tumor stages, and poor differentiation. Accordingly, suppression of GLUT1 expression by siRNA significantly impaired both the growth and migratory potential of HCC cells. Furthermore, inhibition of GLUT1 expression reduced both glucose uptake and lactate secretion. Hypoxic conditions further increased GLUT1 expression levels in HCC cells , and this induction was dependent on the activation of the transcription factor hypoxiainducible factor-1␣. In summary , our findings suggest that increased GLUT1 expression levels in HCC cells functionally affect tumorigenicity , and thus , we propose GLUT1 as an innovative therapeutic target for this highly aggressive tumor. (Am J Pathol

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Distinct temporospatial expression patterns of glycolysis-related proteins in human hepatocellular carcinoma

Daskalow

Pfander²,

Weichert

et al. 2009

Histochem Cell Biol

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Hepatocellular carcinoma (HCC) represents the sixth most frequent human cancer worldwide and is characterized by rapid progression as well as resistance to systemic chemotherapy. Recently, glycolysis has emerged as a potent driving force of tumor growth and therapy failure. The precise role of glycolysis for the pathogenesis of human HCC has not been elucidated thus far. Therefore, we have conducted a comprehensive analysis of the expression patterns of central glycolysis-related factors [glucose transporter-1 and -2 (Glut-1 and Glut-2), phosphoglycerate kinase-1 (PGK-1) and hypoxia-inducible factor-1alpha (HIF-1alpha)] in a large cohort of benign and malignant human liver samples. PGK-1 protein and gene expression was scant in normal liver, elevated in cirrhotic livers and most intense in HCC. Strong immunoreactivity of Glut-2 was noted in cirrhotic livers, whereas in HCC it was only expressed in 50% of examined cases. Strikingly, PGK-1 as well as Glut-2 protein expression was indicative of poor patient prognosis. Glut-1 protein was absent in neoplastic hepatocytes but prominent in tumor-associated endothelial cells. Specific nuclear staining of HIF-1alpha was noted in only 12% of HCC samples. Our data point toward a tumor-promoting function of glycolysis in HCC and establish PGK-1 as an independent prognostic parameter. Furthermore, the endothelial-specific expression of Glut-1 makes a special dependence of vessels on glucose reasonable to assume. In summary, we believe our analysis warrants the validation of glycolytic inhibitors as innovative treatment approaches of human HCC.

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Assessment of Glut-1 expression in cholangiocarcinoma, benign biliary lesions and hepatocellular carcinoma

Cited by 22 publications

References 0 publications

Evaluation of the Role of Hexokinase Type II in Cellular Proliferation and Apoptosis Using Human Hepatocellular Carcinoma Cell Lines

Evaluation of the Role of Hexokinase Type II in Cellular Proliferation and Apoptosis Using Human Hepatocellular Carcinoma Cell Lines

GLUT1 Expression Is Increased in Hepatocellular Carcinoma and Promotes Tumorigenesis

Distinct temporospatial expression patterns of glycolysis-related proteins in human hepatocellular carcinoma

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