Estrogen receptor expression in chronic hepatitis C and hepatocellular carcinoma pathogenesis

Janaki K. Iyer, Mamta Kalra, Anil Kaul, Mark E. Payton, Rashmi Kaul

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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 ERβ, were evaluated by Western blotting and real-time RT-PCR. The subcellular distribution of ERa and ERβ was further determined in nuclear and cytoplasmic tissue lysates along with the expression of inflammatory [activated NF-?B and I?B-kinase (IKK)] and oncogenic (cyclin D1) markers by Western blotting and immunohistochemistry. The expression of ERa and ERβ was correlated with the expression of activated NF-?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 ERa than females (P < 0.05). We observed signifcantly higher mRNA expression of ERa in HCV-related HCC liver tissues as compared to normals (P < 0.05) and ERβ 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 ERβ in HCV-related cirrhosis patients as compared to normals (P < 0.05). Furthermore, we observed a significantly higher expression of phosphorylated NF- ?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 HCVinfection may contribute to the progression of HCVrelated 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 genderrelated disparity in HCV-related pathogenesis.

Original languageEnglish
Pages (from-to)6802-6816
Number of pages15
JournalWorld Journal of Gastroenterology
Volume23
Issue number37
DOIs
StatePublished - 7 Oct 2017

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Chronic Hepatitis C
Estrogen Receptors
Hepacivirus
Hepatocellular Carcinoma
Liver
Cyclin D1
Fibrosis
Liver Diseases
Western Blotting
Tissue Distribution
Cytoplasmic and Nuclear Receptors
Real-Time Polymerase Chain Reaction
Phosphotransferases
Immunohistochemistry
Tissue Donors

Keywords

  • Estrogen receptor a
  • Estrogen receptor β
  • Hepatitis C virus-related cirrhosis
  • Hepatitis C virusrelated hepatocellular carcinoma
  • Normal liver
  • Sex and gender

Cite this

@article{e5027074f21e474183e37339afac0361,
title = "Estrogen receptor expression in chronic hepatitis C and hepatocellular carcinoma pathogenesis",
abstract = "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 ERβ, were evaluated by Western blotting and real-time RT-PCR. The subcellular distribution of ERa and ERβ was further determined in nuclear and cytoplasmic tissue lysates along with the expression of inflammatory [activated NF-?B and I?B-kinase (IKK)] and oncogenic (cyclin D1) markers by Western blotting and immunohistochemistry. The expression of ERa and ERβ was correlated with the expression of activated NF-?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 ERa than females (P < 0.05). We observed signifcantly higher mRNA expression of ERa in HCV-related HCC liver tissues as compared to normals (P < 0.05) and ERβ 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 ERβ in HCV-related cirrhosis patients as compared to normals (P < 0.05). Furthermore, we observed a significantly higher expression of phosphorylated NF- ?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 HCVinfection may contribute to the progression of HCVrelated 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 genderrelated disparity in HCV-related pathogenesis.",
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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.

In: World Journal of Gastroenterology, Vol. 23, No. 37, 07.10.2017, p. 6802-6816.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Estrogen receptor expression in chronic hepatitis C and hepatocellular carcinoma pathogenesis

AU - Iyer, Janaki K.

AU - Kalra, Mamta

AU - Kaul, Anil

AU - Payton, Mark E.

AU - Kaul, Rashmi

PY - 2017/10/7

Y1 - 2017/10/7

N2 - 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 ERβ, were evaluated by Western blotting and real-time RT-PCR. The subcellular distribution of ERa and ERβ was further determined in nuclear and cytoplasmic tissue lysates along with the expression of inflammatory [activated NF-?B and I?B-kinase (IKK)] and oncogenic (cyclin D1) markers by Western blotting and immunohistochemistry. The expression of ERa and ERβ was correlated with the expression of activated NF-?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 ERa than females (P < 0.05). We observed signifcantly higher mRNA expression of ERa in HCV-related HCC liver tissues as compared to normals (P < 0.05) and ERβ 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 ERβ in HCV-related cirrhosis patients as compared to normals (P < 0.05). Furthermore, we observed a significantly higher expression of phosphorylated NF- ?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 HCVinfection may contribute to the progression of HCVrelated 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 genderrelated disparity in HCV-related pathogenesis.

AB - 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 ERβ, were evaluated by Western blotting and real-time RT-PCR. The subcellular distribution of ERa and ERβ was further determined in nuclear and cytoplasmic tissue lysates along with the expression of inflammatory [activated NF-?B and I?B-kinase (IKK)] and oncogenic (cyclin D1) markers by Western blotting and immunohistochemistry. The expression of ERa and ERβ was correlated with the expression of activated NF-?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 ERa than females (P < 0.05). We observed signifcantly higher mRNA expression of ERa in HCV-related HCC liver tissues as compared to normals (P < 0.05) and ERβ 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 ERβ in HCV-related cirrhosis patients as compared to normals (P < 0.05). Furthermore, we observed a significantly higher expression of phosphorylated NF- ?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 HCVinfection may contribute to the progression of HCVrelated 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 genderrelated disparity in HCV-related pathogenesis.

KW - Estrogen receptor a

KW - Estrogen receptor β

KW - Hepatitis C virus-related cirrhosis

KW - Hepatitis C virusrelated hepatocellular carcinoma

KW - Normal liver

KW - Sex and gender

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