Exogenous hepatitis B virus envelope proteins induce endoplasmic reticulum stress: involvement of cannabinoid axis in liver cancer cells

Abstract

HBV represents the most common chronic viral infection and major cause of hepatocellular carcinoma (HCC), although its exact role in liver tumorigenesis is unclear. Massive storage of the small (SHBs), middle (MHBs) and large surface (LHBs) HBV envelope proteins leads to cell stress and sustained inflammatory responses. Cannabinoid (CB) system is involved in the pathogenesis of liver diseases, stimulating acute and chronic inflammation, liver damage and fibrogenesis; it triggers endoplasmic reticulum (ER) stress response. The aim of our work was to investigate the activation of ER stress pathway after ectopic HBV envelope proteins expression, in liver cancer cells, and the role exerted by CB receptors. PCR, immunofluorescence and western blotting showed that exogenous LHBs and MHBs induce a clear ER stress response in Huh-7 cells expressing CB1 receptor. Up-regulation of the chaperone BiP/GRP78 (Binding Immunoglobulin Protein/Glucose-Regulated Protein 78) and of the transcription factor CHOP/GADD153 (C/EBP Homologous Protein/Growth Arrest and DNA Damage inducible gene 153), phosphorylation of PERK (PKR-like ER Kinase) and eIF2α (Eukaryotic Initiation Factor 2α) and splicing of XBP1 (X-box binding protein 1) was observed. CB1−/− HepG2 cells did not show any ER stress activation. Inhibition of CB1 receptor counteracted BiP expression in transfected Huh-7 and in HBV+ PLC/PRF/5 cells; whereas no effect was observed in HBV− HLF cells. These results suggest that HBV envelope proteins are able to induce the ER stress pathway. CB1 expression is directly correlated with ER stress function. Further investigations are needed to clarify the involvement of cannabinoid in HCC progression after HBV infection.

iTRAQ-based high-throughput proteomics analysis reveals alterations of plasma proteins in patients infected with human bocavirus

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Diagnostic and Prognostic Values of MANF Expression in Hepatocellular Carcinoma

“…The liver is an important organ for the synthesis of proteins and lipids, so hepatocyte ER has appropriate adaptive capacity [31]. When the liver is in a state of inflammation for a long time, ER stress is maintained at a high level, which leads to hepatic dysfunction and progression of liver diseases, even HCC [32].…”

“…We selected the median as the group cut-off for survival plots. Upper aerodigestive track (32) Large intestine (60) Pleura (11) Oesophagus (27) Biliary tract 9Autonomic ganglion 17Cervix 2 BioMed Research International for statistical analyses. We select the median expression level for splitting the high-expression and low-expression cohorts.…”

iTRAQ-based Proteomic Analysis of Porcine Kidney Epithelial PK15 cells Infected with Pseudorabies virus

“…ER reside on many molecular chaperones that assist protein folding and assembly 34 . Numerous studies show that viral infections can alter endoplasmic reticulum (ER) and activate the unfolded-protein response (UPR), thereby facilitating viral replication [35][36][37][38] . In the current study, 21 of the differentially expressed proteins were involved in protein processing in the endoplasmic reticulum.…”