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Histochem Cell Biol (2009) 132:2131 DOI 10.1007/s00418-009-0590-4
ORIGINAL PAPER
Distinct temporospatial expression patterns of glycolysis-related proteins in human hepatocellular carcinoma
Katjana Daskalow David Pfander Wilko Weichert Nadine Rohwer Armin Thelen Peter Neuhaus Sven Jonas Bertram Wiedenmann Christoph Benckert Thorsten Cramer
Accepted: 18 March 2009 / Published online: 7 April 2009 Springer-Verlag 2009
Abstract 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-1[afii9825] (HIF-1[afii9825])]
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. SpeciWc nuclear staining of HIF-1[afii9825] 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 endothelialspeciWc 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.
Keywords Glycolysis Hepatocellular carcinoma Hypoxia PGK-1 Glut-1 Glut-2 HIF-1[afii9825]
Introduction
Hepatocellular carcinoma (HCC) is the sixth most common tumor in the world and the most common primary liver cancer (Bosch et al. 2004). The 5-year relative survival rate is t7% and causes more than 600,000 annual deaths worldwide (Bosch et al. 2005). The incidence of HCC has been rising in Europe and Northern America (Bosch et al. 2004; El-Serag and Mason 1999). Recent epidemiological data suggested that the incidence of hepatitis C virus-related HCC will continue to rise over the next...