Sex based relative expression of estrogen receptors and tumor necrosis factor-alpha in liver affects hepatitis C virus viral pathogenesis

World J Gastroenterol. 2025 Aug 28;31(32):104277. doi: 10.3748/wjg.v31.i32.104277.

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

MeSH terms

  • Adult
  • Aged
  • Carcinoma, Hepatocellular* / immunology
  • Carcinoma, Hepatocellular* / metabolism
  • Carcinoma, Hepatocellular* / pathology
  • Carcinoma, Hepatocellular* / virology
  • Estrogen Receptor alpha* / genetics
  • Estrogen Receptor alpha* / metabolism
  • Estrogen Receptor beta* / genetics
  • Estrogen Receptor beta* / metabolism
  • Female
  • Hepacivirus* / immunology
  • Hepacivirus* / pathogenicity
  • Hepatitis C, Chronic* / complications
  • Hepatitis C, Chronic* / immunology
  • Hepatitis C, Chronic* / pathology
  • Hepatitis C, Chronic* / virology
  • Humans
  • Immunity, Innate
  • Liver Cirrhosis* / immunology
  • Liver Cirrhosis* / metabolism
  • Liver Cirrhosis* / pathology
  • Liver Cirrhosis* / virology
  • Liver Neoplasms* / immunology
  • Liver Neoplasms* / metabolism
  • Liver Neoplasms* / pathology
  • Liver Neoplasms* / virology
  • Liver* / immunology
  • Liver* / metabolism
  • Liver* / pathology
  • Liver* / virology
  • Male
  • Middle Aged
  • RNA, Messenger / metabolism
  • Sex Factors
  • Tumor Necrosis Factor-alpha* / genetics
  • Tumor Necrosis Factor-alpha* / metabolism

Substances

  • Tumor Necrosis Factor-alpha
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • ESR1 protein, human
  • ESR2 protein, human
  • RNA, Messenger