Z Gastroenterol 2008; 46 - P2_03
DOI: 10.1055/s-2008-1037511

GLUT1 expression is increased in hepatocellular carcinoma and promotes tumorigenesis

T Amann 1, A Hartmann 2, J Schölmerich 1, A Bosserhoff 2, C Hellerbrand 1
  • 1Klinik und Poliklinik für Innere Medizin I der Universität Regensburg, Regensburg
  • 2Institut für Pathologie der Universität Regensburg, Regensburg

In the 1920s Otto Warburg made the surprising observation that tumor cells utilize glycolysis instead of mitochondrial oxidative phosphorylation for glucose metabolism even when in oxygen-rich conditions. Recently, the "Warburg effect" has a revival since it has been shown that aerobic glycolysis governs tumor cell biology, but studies addressing this issue in hepatocellular carcinoma (HCC) are missing so far.

Here, we analyzed in HCC the expression and function of glucose transporter 1 (GLUT1), which regulates the cellular uptake of glucose, and hexokinase II (HKII) the first enzymes of the glycolytic pathway.

Methods and Results: In HCC tissues and cell lines GLUT1 and HKII expression were significantly higher than in primary human hepatocytes and corresponding non-tumorous tissue, respectively. Immunohistochemical analysis of a tissue microarray containing HCC and corresponding non-cancerous liver tissue of 85 patients confirmed reduced GLUT1 expression in HCC. Additionally, GLUT1 positive HCC tissue showed a significantly higher Ki67 labeling index and was associated with more advanced tumor stages and less differentiated tumor grading. In accordance, suppression of GLUT1 expression in HCC cells by siRNA induced a significantly reduced proliferation and migratory potential in vitro. GLUT1 and HKII are known to be regulated by the transcription factor HIF1alpha, and transfection of HCC-cells with a HIF–1alpha antisense construct abolished GLUT1 expression. In contrast, pharmacological induction of hypoxia further increased HIF1alpha and GLUT1 and HKII expression in HCC cells in vitro.

Summary and Conclusion: Constitutively high HIF1alpha expression in HCC is causing GLUT1 and HKII expression in HCC. The glycolytic pathway is further increased under hypoxic conditions and promotes tumorigenesis in HCC, and herewith, appears as an attractive new therapeutic target for this highly aggressive tumor. Further, our findings have implications for exiting therapies targeting the tumor's oxygen supply as transarterial chemoembolization.