Estrogen receptor expression in chronic hepatitis C and hepatocellular carcinoma pathogenesis

AIM To investigate gender-specific liver estrogen receptor (ER) expression in normal subjects and patients with hepatitis C virus (HCV)-related cirrhosis and hepatocellular carcinoma (HCC). METHODS Liver tissues from normal donors and patients diagnosed with HCV-related cirrhosis and HCV-related HCC were obtained from the NIH Liver Tissue and Cell Distribution System. The expression of ER subtypes, ER alpha and ER beta, were evaluated by Western blotting and real-time RT-PCR. The subcellular distribution of ER alpha and ER beta was further determined in nuclear and cytoplasmic tissue lysates along with the expression of inflammatory [activated NF-kappa B and I kappa B-kinase (IKK)] and oncogenic (cyclin D1) markers by Western blotting and immunohistochemistry. The expression of ER alpha and ER beta was correlated with the expression of activated NF-kappa B, activated IKK and cyclin D1 by Spearman's correlation. RESULTS Both ER subtypes were expressed in normal livers but male livers showed significantly higher expression of ER alpha than females (P < 0.05). We observed significantly higher mRNA expression of ER alpha in HCV-related HCC liver tissues as compared to normals (P < 0.05) and ER beta in livers of HCV-related cirrhosis and HCV-related HCC subjects (P < 0.05). At the protein level, there was a significantly higher expression of nuclear ER alpha in livers of HCV-related HCC patients and nuclear ER beta in HCV-related cirrhosis patients as compared to normals (P < 0.05). Furthermore, we observed a significantly higher expression of phosphorylated NF kappa B and cyclin D1 in diseased livers (P < 0.05). There was a positive correlation between the expression of nuclear ER subtypes and nuclear cyclin D1 and a negative correlation between cytoplasmic ER subtypes and cytoplasmic phosphorylated IKK in HCV-related HCC livers. These findings suggest that dysregulated expression of ER subtypes following chronic HCV-infection may contribute to the progression of HCV-related cirrhosis to HCV-related HCC. CONCLUSION Gender differences were observed in ER alpha expression in normal livers. Alterations in ER subtype expression observed in diseased livers may influence gender-related disparity in HCV-related pathogenesis.