Evidence for Heightened Hexokinase II Immunoexpression in Hepatocyte Dysplasia and Hepatocellular Carcinoma
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Normal hepatocytes exhibit low-affinity hexokinase (glucokinase [HKIV]), but during oncogenesis, there is a switch from HKIV to HKII expression. The aims of this study were to compare the immunoexpression of HKII in non-dysplastic cirrhosis (NDC), liver cell change/dysplasia in cirrhosis (LCD), HCC, and normal liver control tissues, and to correlate HKII expression with clinical and histopathological parameters.
Immunohistochemistry was performed on a liver cancer progression tissue array consisting of specimens from explants with cirrhosis, including 45 tissue samples with HCC, 108 without HCC, 143 with LCD, and 8 normal liver control tissues. HKII expression was quantified as positive pixel counts/square millimeter (ppc/mm2) by image analysis.
There was a stepwise increase in HKII level from normal liver tissue to NDC, to LCD, and to HCC (p = 0.001). HKII levels were significantly higher in areas of LCD versus NDC (p ≤ 0.001), and in LCD and HCC versus NDC (p = 0.007). HKII levels were similar in LCD and HCC (p = 0.124). HKII levels were higher in grade 2–4 versus grade 1 HCCs (p = 0.044), and in pleomorphic versus non-pleomorphic HCC variants (p = 0.041). Higher levels of HKII expression in LCD and HCC versus NDC and in higher tumor grade remained significant in multivariate analysis.
Higher levels of HKII immunoexpression in LDC and HCC compared with NDC suggest that upregulation of HKII occurs during the process of hepatocarcinogenesis in humans. In HCC, higher levels of HKII are associated with more aggressive histological features.
KeywordsHepatocellular carcinoma Liver cell change/dysplasia in cirrhosis Non-dysplastic cirrhosis Hexokinase II immunohistochemistry Tissue microarray Image analysis
This Project was supported by the University of Illinois at Chicago (UIC) Center for Clinical and Translational Sciences (CCTS) to G.G., N.H., and H.X. Award number ULRR029879 from the National Center for Research Resources, by Grants CA090764, AG025953 from the National Institutes of Health to N.H., and VA merit award BX000733 to N.H. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. The authors recognize the contribution of the Research Histology and Tissue Imaging Core at the University of Illinois at Chicago to the completion of this Project (GG/gbg08232014).
Conflict of interest
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