A high rate of glycolysis is one of the earliest discovered hallmarks of cancer. Type II hexokinase (HKII) is the major isozyme overexpressed in tumors with high glycolysis. Aldolase B (AldB) is essential for fructose metabolism, and expresses predominantly in adult liver, whereas aldolase A (AldA) is the major isozyme in hepatocellular carcinoma (HCC). Using differential display analysis to identify aberrant gene expression, AldB was found to be frequently downregulated in HCC. To elucidate the clinicopathological significance in HCC progression and potential molecular mechanisms, we did a comprehensive analysis of the aberrant expressions of AldA, AldB and HKII in relation to various risk factors of HCC progression.

The mRNA levels were measured in 215 surgically removed, unifocal, primary HCCs using the reverse transcription-polymerase chain reaction during the linear range, and correlated with tumor progression indices, particularly portal vein (PV) invasion, early tumor recurrence (ETR), and prognosis of HCC.

AldB mRNA was dramatically decreased in 120 tumors (59%), whereas the mRNA levels of AldA and HKII were increased in 110 (54%) and 82 tumors (40%), respectively. AldB downregulation and HKII overexpression correlated with risk factors of HCC progression, whereas AldA did not. AldB downregulation and HKII overexpression positively correlated with less tumor differentiation (p<0.01 and p<0.002, respectively), high-stage HCC (p=0.00001 and p=0.00002, respectively), ETR (p<0.004 and p<0.002, respectively), and lower 5-year survival rate (p =0.00004 and p=0.0014, respectively). Pair-wise analysis revealed the interaction between AldB downregulation and HK II overexpressions. PV invasion increased by two-fold in HCC with AldB downregulation alone (39%) or HKII overexpression alone (45%), and by 3.5-fold (70%) in HCC positive for both, p<0.000001, as compared to HCC without any of the alterations (20%). In addition, the two aberrant gene expressions also contributed cooperatively to lower 5-year survival, p=0.0014. In conclusion, we demonstrated, for the first time, the downregulation of AldB and HKII overexpression were two important events in the HCC progression, associated with highly metastatic HCC and poor prognosis. The combined analyses of these metabolic alterations help to identify subsets of HCC with high risk of ETR after tumor resection.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA