title: Possible Involvement of Multidrug-Resistant Hepatitis B Virus sW172* Truncation Variant in the ER Stress Signaling Pathway during Hepatocarcinogenesis.
abstract: We investigated the biological effect of hepatitis B virus (HBV) rtA181T/sW172* point mutation on HBsAg secretion and the potential mechanisms involved in hepatocarcinogenesis. Full-length HBV wild type (wt) and HBV rtA181T/sW172* expression plasmids were transfected into HepG2 cell lines or were injected into C57BL/6 mice. The extracellular and intracellular expression levels of HBsAg and HBeAg proteins, in mouse serum and liver tissues were detected by ELISA. The localization of the truncated protein was characterized in vitro. The mRNA expression of endoplasmic reticulum (ER) stress gene GRP78 was determined. HBsAg levels were significantly higher in both supernatant of cells transfected with HBV wt and serum of mice injected with HBV wt, compared with that of HBV rtA181T/sW172* mutant. The reversed trend was observed in intracellular cells and intrahepatic liver cells. Wild type S protein alone could rescue this dysfunction. HBV rtA181T/sW172* truncated surface proteins showed a more aggregated cytoplasmic pattern which were also localized to the ER in comparison with HBV wt. Furthermore, GRP78 mRNA expression was increased 72 h post-transfection in HBV rtA181T/sW172* cells relative to HBV wt cells (P = 0.0154). The HBV sW172* truncation variant has a defect on HBsAg secretion which can lead to surface protein retention in the ER, where it may contribute to hepatocarcinogenesis through activating the ER stress signaling pathway.
authors.affiliation: Department of Laboratory Medicine, Peking University Third Hospital.
authors.forename: Jiajia
authors.initials: J
authors.lastname: Zheng
authors.forename: Suzhen
authors.initials: S
authors.lastname: Jiang
authors.forename: Fengmin
authors.initials: F
authors.lastname: Lu
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D063646:Carcinogenesis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D024921:Drug Resistance, Multiple, Viral / Q000187:drug effects / Q000235:genetics*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics*; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D056945:Hep G2 Cells; D006509:Hepatitis B / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000821:virology; D006514:Hepatitis B Surface Antigens / Q000235:genetics* / Q000378:metabolism; D006513:Hepatitis B e Antigens / Q000235:genetics* / Q000378:metabolism; D006515:Hepatitis B virus / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010957:Plasmids / Q000737:chemistry / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D014162:Transfection
chemical_list: D000998:Antiviral Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D006514:Hepatitis B Surface Antigens; D006513:Hepatitis B e Antigens; C000717248:Hspa5 protein, mouse; D018894:Reverse Transcriptase Inhibitors