Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Oct 7, 2017; 23(37): 6802-6816
Published online Oct 7, 2017. doi: 10.3748/wjg.v23.i37.6802
Estrogen receptor expression in chronic hepatitis C and hepatocellular carcinoma pathogenesis
Janaki K Iyer, Mamta Kalra, Anil Kaul, Mark E Payton, Rashmi Kaul
Janaki K Iyer, Rashmi Kaul, Department of Biochemistry and Microbiology, Oklahoma State University-Center for Health Sciences, Tulsa, OK 74107, United States
Janaki K Iyer, (Current Affiliation) Department of Natural Sciences, Northeastern State University, Tahlequah, OK 74464, United States
Mamta Kalra, Immatics US Inc, Houston, TX 77077, United States
Anil Kaul, Health Care Administration, Oklahoma State University-Center for Health Sciences, Tulsa, OK 74107, United States
Mark E Payton, Department of Statistics, Oklahoma State University, Stillwater, OK 74078, United States
Author contributions: Kaul A and Kaul R designed and coordinated this study; Iyer JK, Kalra M and Kaul R acquired and analyzed the data after performing the molecular investigations; Payton ME performed the statistics on acquired data; Iyer JK, Kalra M, Kaul A and Kaul R contributed to writing and final approval of the article.
Supported by Cancer Sucks, Bixby, Oklahoma Research grant to Kaul R.
Institutional review board statement: The research study protocol was approved by expedited review procedure by the Institutional Review Board of University of Minnesota (FWA 00000312) and Oklahoma State University-Center for Health sciences (2003012-OSU-CHS).
Conflict-of-interest statement: The authors declare no conflict of interest.
Data sharing statement: All available data can be obtained by contacting the corresponding author.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Rashmi Kaul, PhD, Associate Professor, Department of Biochemistry and Microbiology, Oklahoma State University-Center for Health Sciences, Tulsa, OK 74107, United States.
Telephone: +1-918-5611231 Fax: +1-918-5618276
Received: March 20, 2017
Peer-review started: March 22, 2017
First decision: April 21, 2017
Revised: May 12, 2017
Accepted: July 22, 2017
Article in press: July 24, 2017
Published online: October 7, 2017

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).


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, ERα and ERβ, were evaluated by Western blotting and real-time RT-PCR. The subcellular distribution of ERα and ERβ was further determined in nuclear and cytoplasmic tissue lysates along with the expression of inflammatory [activated NF-κB and IκB-kinase (IKK)] and oncogenic (cyclin D1) markers by Western blotting and immunohistochemistry. The expression of ERα and ERβ was correlated with the expression of activated NF-κB, activated IKK and cyclin D1 by Spearman’s correlation.


Both ER subtypes were expressed in normal livers but male livers showed significantly higher expression of ERα than females (P < 0.05). We observed significantly higher mRNA expression of ERα 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 ERα 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-κB 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.


Gender differences were observed in ERα expression in normal livers. Alterations in ER subtype expression observed in diseased livers may influence gender-related disparity in HCV-related pathogenesis.

Keywords: Estrogen receptor α, Estrogen receptor β, Hepatitis C virus-related cirrhosis, Hepatitis C virus-related hepatocellular carcinoma, Sex and gender, Normal liver

Core tip: Our study, for the first time, demonstrates gender-based differences in basal expression of estrogen receptor α (ERα) in the liver of normal males and females. Altered nuclear and cytoplasm liver ER subtype protein expression was also observed in hepatitis C virus (HCV)-cirrhosis and HCV-related hepatocellular carcinoma (HCC) that correlate with the inflammatory and oncogenic markers, activated NF-κB and cyclin D1, implicating their role in chronic cirrhosis and malignant transformation. These findings may have an impact on future planning strategies for the development of novel treatments or prognostic markers by targeting ERs or their signaling pathways during chronic HCV-related cirrhosis and HCC development.