High Level of Hexokinase 2 (HK2) Expression Is Observed in Diabetes, Biologically Aggressive Hepatocellular Carcinomas (HCC), and in the Progression of HCC.
Rohini Chennuri, Alexander Chan, Roshan Patel, Thomas J Layden, Nissim Hay, Scott J Cotler, Grace Guzman. University of Illinois (UIC), Chicago; UIC, Chicago
Background: The mitochondrial high affinity HK2 that catalyzes the first committed step in glycolysis is highly expressed in HCC. Animal studies have shown that normal hepatocytes exhibit only low affinity hexokinase (glucokinase [GK]) but during tumorigenesis, there is a switch from GK to HK2 expression. Aims: To establish the level of HK2 in human liver tissues ranging from cirrhosis to dysplasia & HCC; & to determine whether HK2 expression is associated with clinical parameters or the physical characteristics of the tumor.
Design: We analyzed a liver tissue array derived from 159 subjects with cirrhosis (108 without HCC + 45 with HCC) & 6 with normal liver for the expression of HK2 by standard immunohistochemistry. Cytoplasmic HK2 positivity was quantified by image analysis in normal, cirrhosis, dysplasia, & HCC. One-way ANOVA & independent samples t-tests for normally distributed groups, Kruskal-Wallis tests & Mann-Whitney U tests for non-normally distributed groups, were employed using SPSS Statistics 17.0.
Results: The HK2 mean level in normal liver was 36.67 (±15.20;n=6), cirrhosis 44.18 (±32.71;n=106), dysplasia 59.94 (±39.86;n=143), & HCC 64.42 (±34.89;n=45). In the cirrhosis without HCC group, we found that the HK2 level was higher in dysplasia in DM(+)(82.21) vs DM(-) subjects (56.18)(p=0.018). In areas of dysplasia, advanced stage HCCs (stage III & IV) have a higher level of HK2 (87.88) in comparison to low stage HCCs (stage 1, 41.34)(p=0.023). In the HCC group, HK2 expression was higher in poorly differentiated tumors (73.77) in comparison to well differentiated (47.18) and moderately differentiated tumors (70.97)(p=0.033), & in pleomorphic variant (85.82) vs non-pleomorphic HCC variants (57.03)(p=0.008). In the cirrhosis without HCC group, HK2 expression was higher in dysplasia (61.76) in comparison to cirrhosis (46.54)(p=0.005). In the HCC group, HK2 expression was peak in carcinoma (64.42), followed by dysplasia (56.00) & cirrhosis (37.26)(p=0.007).
Conclusions: This study shows that the level of HK2 is higher in DM(+) subjects, & in biologically aggressive HCCs. Moreover, HK2 may be an important biomarker for assessing the progression of cirrhosis to dysplasia and HCC. Verification of the findings in this study using a larger cohort is necessary to determine whether HK2 is biomarker for hepatocarcinogenesis.
Category: Liver & Pancreas
Monday, February 28, 2011 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 200, Monday Morning