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.