Key Takeaways & Executive Findings
- •• HEV infection significantly upregulates ING5 expression in both acute (BALB/c mice) and chronic (rhesus macaques) animal models, as well as in human hepatoma cells (HepG-2). • This is the first study to demonstrate a direct link between HEV infection and ING5, a tumor suppressor, suggesting a potential mechanism for HEV-associated hepatocarcinogenesis. • The findings provide novel insights into the pathogenic mechanisms of HEV infection, particularly in immunocompromised patients at risk for chronic hepatitis and HCC. • The upregulation of ING5 during HEV infection may represent a host defense response or a viral manipulation strategy, warranting further investigation for therapeutic targeting.
Abstract
Hepatitis E virus (HEV) is the major pathogen of viral hepatitis. Immunocompromised individuals infected by HEV are prone to chronic hepatitis and increase the risk of hepato-cellular carcinoma (HCC). Inhibitor of growth family member 5 (ING5) is a tumor suppressor that is expressed at low levels in cancer tumors or cells. However, the underlying relationship between ING5 and HEV infection is unclear. In the present study, acute and chronic HEV animal models are used to explore the interaction between ING5 and HEV. Notably, the expression of ING5 is significantly increased in both the livers of acute HEV-infected BALB/c mice and chronic HEV-infected rhesus macaques. In addition, the relationship between HEV infection and ING5 expression is further identified in human hepatoma (HepG-2) cells. In conclusion, HEV infection strongly upregulates ING5 expression both in vivo and in vitro, which has significant implications for further understanding the pathogenic mechanism of HEV infection.
1. Introduction
Hepatitis E virus (HEV) is the most common cause of acute viral hepatitis worldwide [1]. HEV infection usually causes acute self-limiting diseases with low mortality in the general population but leads to approximately 25% maternal death in pregnant women [2–4]. Importantly, chronic HEV infection has been reported in immunocompromised patients, such as organ-transplant recipients [5,6], HIV-infected patients and cancer patients receiving chemotherapy [7]. HEV infection increases the risk of liver decompensation in patients with underlying chronic liver disease, including non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD) and chronic hepatitis C virus (HCV) [8–12], and aggravates the development of hepato-cellular carcinoma (HCC) in chronic hepatitis B virus (HBV)-infected patients. However, the pathogenesis by which HEV infection promotes the development of HCC is still unclear.
The inhibitor of growth (ING) family (members 1-5) plays important roles in the cell cycle, cell proliferation and growth, apoptosis and senescence [13,14]. The ING family has been identified to be a tumor suppressor gene (TSG) family that interacts with the determinants of chromatin function and gene-specific transcription factors [13]. ING5 encodes a tumor suppressor protein that inhibits cell growth and induces apoptosis [13]. It contains a PHD-type zinc finger and interacts with the tumor suppressors p53 and p300, which are components of the histone acetyltransferase complex, indicating a role in transcriptional regulation [15,16]. ING5 plays a crucial role in chromatin acetylation, oncogenic transformation and cancer development [16]. In cancer cells, ING5 transcript levels are often suppressed; for example, low expression of ING5 was found in esophageal squamous cell carcinoma (ESCC) [17], and suppressed ING5 was reported in HBV-induced HCC [18,19]. The mechanism underlying the suppression of ING5 expression may involve abnormally high methylation level of the ING gene promoter, which are correlated with low transcript levels [13]. Thus, ING5 is considered to be a promising target for cancer treatment.
HEV infection in immunocompromised patients can lead to chronic hepatitis and progression to cirrhosis [20,21]. However, whether ING5 is regulated during HEV infection is still unknown. In the present study, the expression of ING5 in an acute HEV infection animal model and a chronic HEV infection animal model was assessed to explore the potential regulatory relationship between HEV and ING5, providing novel insights into the pathogenic mechanisms of HEV infection.
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Wanqiu Zhao, Yueping Xia, Tengyuan Li, Huichan Liu, Guo Zhong, Dongxue Chen, Wenhai Yu, Yunlong Li, Fen Huang (2026). Hepatitis E virus infection upregulates ING5 expression in vitro and in vivo. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2024091
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Frequently Asked Questions
What is the main finding of this study?
The study demonstrates that Hepatitis E virus (HEV) infection significantly upregulates the expression of ING5, a tumor suppressor protein, in both in vivo models (BALB/c mice and rhesus macaques) and in vitro (HepG-2 cells).
Why is ING5 important in the context of HEV infection?
ING5 is a tumor suppressor that is often downregulated in cancers. Its upregulation during HEV infection may play a role in the host's antiviral response or contribute to the pathogenesis of HEV-associated liver disease, including hepatocellular carcinoma.
What animal models were used in this study?
The study used BALB/c mice for acute HEV infection and rhesus macaques for chronic HEV infection to assess ING5 expression in liver tissues.
What are the potential clinical implications of this research?
Understanding the relationship between HEV and ING5 could provide new insights into the mechanisms of HEV-induced liver damage and cancer, potentially leading to novel therapeutic targets for chronic HEV infection and associated HCC.
How was ING5 expression measured?
ING5 expression was assessed in liver tissues from infected animals and in HepG-2 cells using techniques such as quantitative real-time PCR (qRT-PCR), western blot analysis, and immunofluorescence assay (IFA).
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