Glucose-regulated protein 78 demonstrates antiviral effects but is more suitable for hepatocellular carcinoma prevention in hepatitis B

Nai Q Zheng,Zi H Zheng,Hai X Xu,Xiao M Peng,Ming X Huang

doi:10.1186/s12985-017-0747-z

Abstract

BackgroundHepatitis B virus (HBV) is the leading cause of liver cirrhosis and hepatocellular carcinoma in Asia and Africa. Existing antivirals cannot cure HBV or eliminate risk of hepatocellular carcinoma. Glucose-regulated protein 78 (GRP78) can inhibit HBV replication, but promote virion secretion and hepatocellular cancer cell invasion. For these reasons, the overall effect of GRP78 on HBV production and whether to utilize the HBV replication-inhibitory effect of GRP78 up-regulation or the hepatocellular cancer cell invasion-inhibitory effect of its down-regulation were further investigated in order to improve the efficacy of current antiviral therapy.MethodsGRP78 regulations in HepG2.2.15 cells were conducted by transfections of expressing vector and small interfering RNA, respectively. The changes in HBV replication, hepatitis B e antigen (HBeAg) synthesis and hepatoma cell motility were monitored.ResultsGRP78 overall decreased HBV production due to its HBV replication-inhibitory effect time-dependently overwhelming virion secretion-promoting effect in HepG2.2.15 cells. Unlike the parental cells (HepG2), HepG2.2.15 cells demonstrated decreased expressions of the major genes in the interferon-β1-dependent pathway. Moreover, the expressions of these genes were not affected by GRP78 regulations. However, GRP78 was found to inhibit HBeAg secretion and to increase the retro-transportation of capsid assembly-interfering HBeAg precursor from the endoplasmic reticulum into the cytosol where new viral nucleocapsids formed. Furthermore, GRP78 overexpression promoted wound healing process (the motility) of HepG2.2.15 cells. In contrast, GRP78 knockdown enhanced HBV replication and HBeAg secretion, but they were abolished by entecavir and furin inhibitor, respectively.ConclusionsGRP78 mainly demonstrates anti-HBV effects, reducing HBV production and HBeAg secretion. With due regard to the hepatocellular cancer invasion risk of the overexpression and the rectifiability of the unpleasant effects of the knockdown, GRP78 down-regulation may be more suitable to serve as an additive strategy to cover the hepatocellular cancer prevention shortage of current antiviral therapy in the future.

Highlights

Hepatitis B virus (HBV) is the leading cause of liver cirrhosis and hepatocellular carcinoma in Asia and Africa
Glucose-regulated protein 78 (GRP78) overwhelms its viral secretion-promoting effect to suppress HBV production in HepG2.2.15 cells GRP78 has been reported to promote the secretion of HBV particles in HepG2.2.15 cells, but to act as an intracellular anti-HBV factor in HepAD38, a cell line with Tetoff promoter to control its HBV production [22,23,24]
HepG2.2.15 cells were used in this study to clarify the overall effect of GRP78 on HBV production

Summary

Introduction

Hepatitis B virus (HBV) is the leading cause of liver cirrhosis and hepatocellular carcinoma in Asia and Africa. Antiviral therapy based on current options, recombinant interferon (IFN)-α and nucleotide/nucleoside analogs, has markedly reduced the incidence of liver cirrhosis and HCC [3, 4]. It hardly eliminates HBV infection and the suppression of viral replication below the limit of detection does not completely prevent HCC development liver fibrosis can be stopped [4, 5]. It remains imperative to search for new therapeutic targets against HBV infection or HCC development

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