Association of the Hepatitis B Virus Large Surface Protein with Viral Infectivity and Endoplasmic Reticulum Stress-mediated Liver Carcinogenesis.

Wei-Ling Lin,Wenya Huang,Jui-Hsiang Hung

doi:10.3390/cells9092052

Abstract

Hepatitis B is the most prevalent viral hepatitis worldwide, affecting approximately one-third of the world’s population. Among HBV factors, the surface protein is the most sensitive biomarker for viral infection, given that it is expressed at high levels in all viral infection phases. The large HBV surface protein (LHBs) contains the integral pre-S1 domain, which binds to the HBV receptor sodium taurocholate co transporting polypeptide on the hepatocyte to facilitate viral entry. The accumulation of viral LHBs and its prevalent pre-S mutants in chronic HBV carriers triggers a sustained endoplasmic reticulum (ER) overload response, leading to ER stress-mediated cell proliferation, metabolic switching and genomic instability, which are associated with pro-oncogenic effects. Ground glass hepatocytes identified in HBV-related hepatocellular carcinoma (HCC) patients harbor pre-S deletion variants that largely accumulate in the ER lumen due to mutation-induced protein misfolding and are associated with increased risks of cancer recurrence and metastasis. Moreover, in contrast to the major HBs, which is decreased in tumors to a greater extent than it is in peritumorous regions, LHBs is continuously expressed during tumorigenesis, indicating that LHBs serves as a promising biomarker for HCC in people with CHB. Continuing efforts to delineate the molecular mechanisms by which LHBs regulates pathological changes in CHB patients are important for establishing a correlation between LHBs biomarkers and HCC development.

Highlights

Chronic hepatitis B (CHB) virus infection is the most important cause of hepatocellular carcinoma (HCC) worldwide
Signaling pathway causes the sterol regulatory element binding transcription factor 1 (SREBF1)-induced upregulation of ATP citrate lyase (ACLY) and fatty acid desaturase 2 (FADS2), leading to an increase in triglycerides and cholesterol [77]. These findings clearly indicate that large HBV surface protein (LHBs)-induced endoplasmic reticulum (ER) stress-mediated lipid metabolism disturbance is functionally linked to HBV tumorigenesis
A later study by Wang et al [46] showed that ground glass hepatocytes (GGHs) harbor pre-S deletion variants that accumulate in the ER and induce ER stress signaling

Summary

Introduction

Chronic hepatitis B (CHB) virus infection is the most important cause of hepatocellular carcinoma (HCC) worldwide. 2 billion people, has been infected with HBV, and more than 200 million people suffer from CHB [1]. Individuals with CHB are at a greater than 100-fold increased risk of developing advanced liver diseases, including cirrhosis and HCC [2,3]. HCC remains among the leading causes of cancer death worldwide. Effective prevention and control of HBV infection are very important public health issues in countries with epidemic HBV. In some regions, such as South Korea, Singapore and Taiwan, where the nationwide HBV vaccination of newborns has been executed for a few decades, Cells 2020, 9, 2052; doi:10.3390/cells9092052 www.mdpi.com/journal/cells

Glycosylations of the LHBs Pre-S Regions that Regulate Protein Topology

The Pre-S1 Domain of the HBV Large Surface Protein in Viral Entry

ER Stress-mediated Metabolic Pathways Associated with LHBs

Pre-S1 Deletion Variants

Pre-S2 Deletion Variants

LHBs in Infection Phases and HCC

Findings

Conclusions