Basic Study
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Aug 28, 2025; 31(32): 104277
Published online Aug 28, 2025. doi: 10.3748/wjg.v31.i32.104277
Sex based relative expression of estrogen receptors and tumor necrosis factor-alpha in liver affects hepatitis C virus viral pathogenesis
Sarah Groover, Sarah Addison, Savannah Nicks, Mitchelle Mwangi, Amy Brooks, Anil Kaul, Rashmi Kaul
Sarah Groover, Sarah Addison, Savannah Nicks, Mitchelle Mwangi, Amy Brooks, Rashmi Kaul, Department of Biochemistry and Microbiology, Oklahoma State University Center for Health Sciences, Tulsa, OK 74017, United States
Sarah Groover, Department of Family and Community Medicine, University of New Mexico, Albuquerque, NM 87106, United States
Anil Kaul, Health Care Administration, Oklahoma State University Center for Health Sciences, Tulsa, OK 74017, United States
Author contributions: Groover S, Kaul R and Kaul A designed and coordinated the study; Groover S, Addison S, Nicks S, Mwangi M, and Brooks A performed the experiments, acquired and analyzed data; Groover S and Kaul R interpreted the data; Groover S, Kaul R, Addison S, Nicks, S, Mwangi M, and Brooks A wrote the manuscript; All authors approved the final version of the article.
Supported by Cancer Sucks, Bixby, Oklahoma Research Grant.
Institutional review board statement: The study received approval from the Institutional Review Board at the University of Minnesota under Exemption IV (No. 2023012).
Institutional animal care and use committee statement: This study does not involve any animal experiments.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
Data sharing statement: No additional data are available.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (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: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Rashmi Kaul, PhD, Professor, Department of Biochemistry and Microbiology, Oklahoma State University Center for Health Sciences, 1111 W 17th St, Tulsa, OK 74017, United States. rashmi.kaul10@okstate.edu
Received: December 16, 2024
Revised: March 27, 2025
Accepted: August 6, 2025
Published online: August 28, 2025
Processing time: 254 Days and 6.3 Hours
Abstract
BACKGROUND

Hepatocellular carcinoma (HCC) is a global health concern, representing the second most common cause of malignancy-related mortality in the world. The primary cause of HCC in the United States is chronic infection with the hepatitis C virus (HCV). Clinical observations have established sex-based differences in HCV infection with the disease progressing more severely and more rapidly in males and postmenopausal females compared to premenopausal females, suggesting that estrogens and their receptors may play an important role in hepatic defenses and development of HCV-mediated HCC. However, the precise mechanism of estrogen protection and their effects on inflammation is poorly understood.

AIM

To determine whether estrogen receptor (ER) expression is correlated with the expression of tumor necrosis factor-alpha (TNF-α) in males and females with HCV-associated diseases.

METHODS

The role of ERs in modulating innate immune responses was investigated using human liver tissues with HCV/cirrhosis and HCV/HCC. Messenger RNA (mRNA) and protein (nuclear and cytoplasmic) expression were measured for all markers of interest and compared to normal human liver tissue samples.

RESULTS

ERβ was reported for the first time to have a greater mRNA expression than ERα in normal liver (P ≤ 0.001). In addition, ERβ mRNA expression was found to be decreased in diseased livers (P ≤ 0.05), while TNF-α expression was increased (P ≤ 0.0001). Upon stratifying by sex within each disease group, ESR1 was found to be negatively correlated with ESR2 in females with HCV/cirrhosis (r = -0.84, P ≤ 0.001), whereas males with HCV/cirrhosis were found to have a significant positive correlation (r = 0.57, P ≤ 0.05). ESR2 mRNA expression had a significant positive correlation with TNF-α in both HCV/cirrhosis (r = 0.61, P ≤ 0.001) and HCV/HCC patients (r = 0.45, P ≤ 0.05).

CONCLUSION

All together, these findings indicate that changes in ERβ and TNF-α expression are associated with worsening disease, and may be part of the sex-dependent factors in HCC pathogenesis.

Keywords: Hepatocellular carcinoma; Hepatitis C virus; Inflammation; Estrogen receptor; Liver cirrhosis; Tumor necrosis factor alpha

Core Tip: Our study, for the first time, demonstrates an increase in expression of estrogen receptor (ER) β compared to ERα in the liver of normal males and females. In addition, ERβ message RNA expression was found to be decreased in hepatitis C virus (HCV)/cirrhosis and HCV/hepatocellular carcinoma livers, while tumor necrosis factor-α expression was increased. Further analysis of the data revealed sex-specific correlations between ERα and ERβ. These findings suggest that changes in ERβ expression are associated with worsening HCV-related disease, and may be one of the sex-dependent factors in cirrhosis and hepatocellular carcinoma pathogenesis.