Roles of Copper in Hepatocarcinogenesis via the Activation of Hypoxia-Inducible Factor-1α.

Abstract

Hypoxia-inducible factor-1α (HIF-1α) is involved in the pathogenesis of hepatocellular carcinoma (HCC). However, the roles of trace elements in the activation of HIF-1α during hepatocarcinogenesis have been unclear. We investigated whether copper (Cu) and zinc (Zn) participated in the activation of HIF-1α in the process of hepatocarcinogenesis or not. Nine patients with chronic hepatitis (CH), five with liver cirrhosis (LC), 12 with HCC, and nine normal healthy controls were enrolled in this study. Their serum HIF-1α, Cu, and Zn levels were determined in the enrolled patients. Hepatic HIF-1α expression was evaluated, using an immunohistochemical procedure. The HCC patients had significantly higher serum HIF-1α levels than the CH patients (6.47±1.57 vs. 5.09±1.22ng/ml, p=0.0344). The serum Cu level in the HCC patients was also significantly higher than those in the CH and LC patients (137±24 vs. 107±15μg/dl, 114±24μg/dl). Interestingly, a positive correlation was observed between serum HIF-1α and Cu levels in the enrolled patients (r=0.425, p=0.0137). In contrast, no significant differences in serum Zn levels were present between the HCC patients and the CH or LC patients. The serum HIF-1α was not positively correlated with the serum Zn level in the enrolled patients, either. Immunohistochemical analysis revealed that two of the five HCC patients had HIF-1α expression in the tumor tissues, whereas none of CH and LC had hepatic HIF-1α expression in the liver tissues. These data suggest that the activation of HIF-1α derived from a Cu accumulation in the liver may cause hepatocarcinogenesis.