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

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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-1α (HIF-1α)] 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-1α 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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Acknowledgments

This study was supported by grants from the Deutsche Forschungsgemeinschaft (CR 133/2-2) and the Berliner Krebsgesellschaft (CRFF200804) to Thorsten Cramer. Nadine Rohwer was supported by grants from the Deutsche Forschungsgemeinschaft (Graduiertenkolleg 276/4). The excellent technical assistance of Birgit Bogdanoff is highly appreciated.

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Authors and Affiliations

  1. Medizinische Klink mit Schwerpunkt Hepatologie und Gastroenterologie, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany

    Katjana Daskalow, Nadine Rohwer, Bertram Wiedenmann & Thorsten Cramer

  2. Abteilung für orthopädische Rheumatologie, Klinik für Orthopädie und Unfallchirurgie, Hufeland Klinikum, Mühlhausen, Germany

    David Pfander

  3. Institut für Pathologie, Charité-Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany

    Wilko Weichert

  4. Chirurgische Klinik II, Visceral-, Transplantations-, Thorax- und Gefässchirurgie, Universitätsklinikum Leipzig, Leipzig, Germany

    Armin Thelen, Sven Jonas & Christoph Benckert

  5. Klinik für Allgemein-, Visceral- und Transplantationschirurgie, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany

    Peter Neuhaus

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  1. Katjana Daskalow
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  2. David Pfander
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  4. Nadine Rohwer
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  5. Armin Thelen
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  8. Bertram Wiedenmann
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  9. Christoph Benckert
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  10. Thorsten Cramer
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Correspondence to Thorsten Cramer.

Additional information

Christoph Benckert and Thorsten Cramer have contributed equally to this work.

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Daskalow, K., Pfander, D., Weichert, W. et al. Distinct temporospatial expression patterns of glycolysis-related proteins in human hepatocellular carcinoma. Histochem Cell Biol 132, 21–31 (2009). https://doi.org/10.1007/s00418-009-0590-4

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