Choline kinase alpha and hexokinase-2 protein expression in hepatocellular carcinoma: association with survival

Abstract

Purpose: Hexokinase-2 (HK2) and more recently choline kinase alpha (CKA) expression has been correlated with clinical outcomes in several major cancers. This study examines the protein expression of HK2 and CKA in hepatocellular carcinoma (HCC) in association with patient survival and other clinicopathologic parameters.

Methods: Immunohistochemical analysis for HK2 and CKA expression was performed on a tissue microarray of 157 HCC tumor samples. Results were analyzed in relation to clinicopathologic data from Surveillance, Epidemiology, and End-Results Program registries. Mortality rates were assessed by Kaplan-Meier estimates and compared using log-rank tests. Predictors of overall survival were assessed using proportional hazards regression.

Results: Immunohistochemical expression of HK2 and CKA was detected in 71 (45%) and 55 (35%) tumor samples, respectively. Differences in tumor HK2 expression were associated with tumor grade (p = 0.008) and cancer stage (p = 0.001), while CKA expression differed significantly only across cancer stage (p = 0.048). Increased mortality was associated with tumor HK2 expression (p = 0.003) as well as CKA expression (p = 0.03) with hazard ratios of 1.86 (95% confidence interval (CI) 1.23-2.83) and 1.59 (95% CI 1.04-2.41), respectively. Similar effects on overall survival were noted in a subset analysis of early stage (I and II) HCC. Tumor HK2 expression, but not CKA expression, remained a significant predictor of survival in multivariable analyses.

Conclusion: HK2 and CKA expression may have biologic and prognostic significance in HCC, with tumor HK2 expression being a potential independent predictor of survival.

Figure 1. Photomicrographs of HCC tissue specimens stained using anti-CKA antibody.

Images magnified at 200×. A) Normal liver tissue demonstrates an absence of immunohistochemical staining. B) Corresponding HCC tumor specimen from the same patient demonstrates mild cytoplasmic staining of moderately-differentiated tumor cells. C) Moderately-differentiated HCC nested within an area of fibrosis. The tumor cells demonstrate moderate cytoplasmic and nuclear staining.

Figure 2. Patterns of overall survival (OS) based on tumor immunohistochemical expression of CKA and HK2.

Solid lines represent immunohistochemistry-positive cases while dotted lines represent immunohistochemistry-negative cases. A) OS was significantly worse for patients with CKA-positive tumors relative to patients with CKA-negative tumors (Log-Rank test p = 0.03). B) OS was also significantly worse for patients with HK2-positive tumors relative to patients with HK2-negative tumors (Log-Rank test p = 0.003). C) Among stage I and II HCC patients, OS was significantly worse for patients with CKA-positive tumors relative to patients with CKA-negative tumors (Log-rank p = 0.03). D) Among stage I and II HCC patients, OS was also significantly worse for patients with HK2-positive tumors relative to patients with HK2-negative tumors (Log-rank p = 0.02). E) Among patients with HK2-negative tumors, OS did not differ significantly on the basis of CKA expression (Log-Rank test p = 0.53). F) Among patients with HK2-positive tumors, OS was significantly worse in patients whose tumors were also CKA-positive (Log-Rank test p = 0.04). G) Among patients with CKA-negative tumors, OS did not differ significantly on the basis of HK2 expression (Log-Rank test p = 0.35). H) Among patients with CKA-positive tumors, OS was significantly worse in patients whose tumors were also HK2-positive (Log-Rank test p = 0.01).