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Hepatology ; 74(2): 641-655, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-33675094

RESUMEN

BACKGROUND AND AIMS: PreS mutants of HBV have been reported to be associated with HCC. We conducted a longitudinal study of the role of HBV preS mutations in the development of HCC, particularly in patients with chronic hepatitis B (CHB) having low HBV DNA or alanine aminotransferase (ALT) levels, and investigated the effects of secretion-defective preS2 deletion mutant (preS2ΔMT) on hepatocyte damage in vitro and liver fibrosis in vivo. APPROACH AND RESULTS: Association of preS mutations with HCC in 343 patients with CHB was evaluated by a retrospective case-control follow-up study. Effects of preS2ΔMT on HBsAg retention, endoplasmic reticulum (ER) stress, calcium accumulation, mitochondrial dysfunction, and liver fibrosis were examined. Multivariate analysis revealed a significant association of preS mutations with HCC (HR, 3.210; 95% CI, 1.072-9.613; P = 0.037) including cases with low HBV DNA or ALT levels (HR, 2.790; 95% CI, 1.133-6.873; P = 0.026). Antiviral therapy reduced HCC risk, including cases with preS mutations. PreS2ΔMT expression promoted HBsAg retention in the ER and unfolded protein response (UPR). Transmission electron microscopic examination, MitoTracker staining, real-time ATP assay, and calcium staining of preS2ΔMT-expressing cells revealed aberrant ER and mitochondrial ultrastructure, reduction of mitochondrial membrane potential and ATP production, and calcium overload. Serum HBV secretion levels were ~100-fold lower in preS2ΔMT-infected humanized Fah-/-/ Rag2-/-/Il2rg-/- triple knockout mice than in wild-type HBV-infected mice. PreS2ΔMT-infected mice displayed up-regulation of UPR and caspase-3 and enhanced liver fibrosis. CONCLUSIONS: PreS mutations were significantly associated with HCC development in patients with CHB, including those with low HBV DNA or ALT levels. Antiviral therapy reduced HCC occurrence in patients with CHB, including those with preS mutations. Intracellular accumulation of mutated HBsAg induced or promoted ER stress, calcium overload, mitochondrial dysfunction, impaired energy metabolism, liver fibrosis, and HCC.


Asunto(s)
Carcinoma Hepatocelular/epidemiología , Antígenos de Superficie de la Hepatitis B/genética , Virus de la Hepatitis B/inmunología , Hepatitis B Crónica/inmunología , Cirrosis Hepática/epidemiología , Neoplasias Hepáticas/epidemiología , Precursores de Proteínas/genética , Adulto , Animales , Antivirales/uso terapéutico , Carcinogénesis/inmunología , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/virología , Estudios de Casos y Controles , Modelos Animales de Enfermedad , Femenino , Estudios de Seguimiento , Antígenos de Superficie de la Hepatitis B/inmunología , Virus de la Hepatitis B/genética , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/patología , Hepatitis B Crónica/virología , Hepatocitos/trasplante , Interacciones Huésped-Patógeno/genética , Humanos , Cirrosis Hepática/inmunología , Cirrosis Hepática/patología , Cirrosis Hepática/virología , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/virología , Estudios Longitudinales , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Mitocondrias Hepáticas/patología , Mutación , Precursores de Proteínas/inmunología , Estudios Retrospectivos , Quimera por Trasplante
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