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Estrogen receptor expression in chronic hepatitis C and hepatocellular carcinoma pathogenesis

Iyer, Janaki K.
Kalra, Mamta
Kaul, Anil
Payton, Mark E.
Kaul, Rashmi
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, ERa and ERB, were evaluated by Western blotting and real-time RT-PCR. The subcellular distribution of ERa and ERB was further determined in nuclear and cytoplasmic tissue lysates along with the expression of inflammatory [activated NF-KB and IKB-kinase (IKK)] and oncogenic (cyclin D1) markers by Western blotting and immunohistochemistry. The expression of ERa and ERB was correlated with the expression of activated NF-KB, 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 ERa than females (P < 0.05). We observed significantly higher mRNA expression of ERa in HCV-related HCC liver tissues as compared to normals (P < 0.05) and ERB 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 ERa in livers of HCV-related HCC patients and nuclear ERB in HCV-related cirrhosis patients as compared to normals (P < 0.05). Furthermore, we observed a significantly higher expression of phosphorylated NF-KB 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 ERa expression in normal livers. Alterations in ER subtype expression observed in diseased livers may influence gender-related disparity in HCV-related pathogenesis.