Hexokinase II and VEGF expression in liver tumors: correlation with hypoxia-inducible factor 1 alpha and its significance

J Hepatol. 2004 Jan;40(1):117-23. doi: 10.1016/s0168-8278(03)00503-8.


Background/aims: We analyzed the expressions of hexokinase II (HK II), a key enzyme in glycolysis, and VEGF in hepatocellular carcinoma (HCC) and metastatic liver cancer in relation to tumor vascularity, and the participation of hypoxia-inducible factor-1 (HIF-1) was studied.

Methods: A real-time quantitative reverse transcription-polymerase chain reaction was performed to examine the HK II and VEGF mRNA expression. Expression of HIF-1 alpha and HK II protein, and microvessel density (MVD) were examined immunohistochemically.

Results: MVD was significantly higher in HCCs than in metastatic liver cancers, and VEGF mRNA expression was positively correlated only with MVD of HCCs. HK II mRNA expression was significantly higher in metastatic liver cancers, however, some cases of HCC pretreated with transcatheter arterial embolization (TAE) showed marked HK II mRNA expression. Both HIF-1 alpha and HK II protein expressions were co-localized in the cancer cells near necrosis, and the intensity of HIF-1 alpha protein expression was significantly correlated with HK II mRNA expression in both tumors.

Conclusions: These results suggest that, in metastatic liver cancers, glycolysis induced by HIF-1 is the predominant energy source under the hypoxic environment and, at least in some TAE-pretreated HCC cases, cancer cells obtain energy for growth by switching the metabolic profile to glycolysis through HIF-1.

MeSH terms

  • Aged
  • Blood Vessels / pathology
  • Carcinoma, Hepatocellular / blood supply
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / secondary*
  • Colorectal Neoplasms / pathology
  • Computer Systems
  • Female
  • Hexokinase / genetics
  • Hexokinase / metabolism*
  • Humans
  • Immunohistochemistry
  • Liver Neoplasms / blood supply
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / secondary*
  • Male
  • Microcirculation
  • Middle Aged
  • Mixed Function Oxygenases
  • Polymerase Chain Reaction / methods
  • Proliferating Cell Nuclear Antigen / metabolism
  • RNA, Messenger / metabolism
  • Repressor Proteins / metabolism*
  • Transcription Factors / metabolism*
  • Vascular Endothelial Growth Factor A / metabolism*
  • von Willebrand Factor / metabolism


  • Proliferating Cell Nuclear Antigen
  • RNA, Messenger
  • Repressor Proteins
  • Transcription Factors
  • Vascular Endothelial Growth Factor A
  • von Willebrand Factor
  • Mixed Function Oxygenases
  • HIF1AN protein, human
  • Hexokinase