Novel HBsAg mutations correlate with hepatocellular carcinoma, hamper HBsAg secretion and promote cell proliferation in vitro

BACKGROUND: An impaired HBsAg-secretion can increase HBV oncogenic-properties. Here, we investigate genetic-determinants in HBsAg correlated with HBV-induced hepatocellular carcinoma (HCC), and their impact on HBsAg-secretion and cell-proliferation. METHODS: This study included 128 chronically HBV-i...

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Detalles Bibliográficos
Autores principales: Salpini, Romina, Surdo, Matteo, Warner, Nadia, Cortese, Maria Francesca, Colledge, Danny, Soppe, Sally, Bellocchi, Maria Concetta, Armenia, Daniele, Carioti, Luca, Continenza, Fabio, Carlo, Domenico Di, Saccomandi, Patrizia, Mirabelli, Carmen, Pollicita, Michela, Longo, Roberta, Romano, Sara, Cappiello, Giuseppina, Spanò, Alberto, Trimoulet, Pascale, Fleury, Herve, Vecchiet, Jacopo, Iapadre, Nerio, Barlattani, Angelo, Bertoli, Ada, Mari, Terenzio, Pasquazzi, Caterina, Missale, Gabriele, Sarrecchia, Cesare, Orecchini, Elisa, Michienzi, Alessandro, Andreoni, Massimo, Francioso, Simona, Angelico, Mario, Verheyen, Jens, Ceccherini-Silberstein, Francesca, Locarnini, Stephen, Perno, Carlo Federico, Svicher, Valentina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Research Paper
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5362517/
https://www.ncbi.nlm.nih.gov/pubmed/28152517
http://dx.doi.org/10.18632/oncotarget.14944
Descripción
Sumario:BACKGROUND: An impaired HBsAg-secretion can increase HBV oncogenic-properties. Here, we investigate genetic-determinants in HBsAg correlated with HBV-induced hepatocellular carcinoma (HCC), and their impact on HBsAg-secretion and cell-proliferation. METHODS: This study included 128 chronically HBV-infected patients: 23 with HCC (73.9% D; 26.1% A HBV-genotype), and 105 without cirrhosis/HCC (72.4% D, 27.6% A) as reference-group. The impact of mutations on HBsAg-secretion was assessed by measuring the ratio [secreted/intracellular HBsAg] until day 5 post-transfection. The impact of mutations on cell-cycle advancement was assessed by flow-cytometry. RESULTS: Two HBsAg mutations significantly correlated with HCC: P203Q (17.4% [4/23] in HCC vs 1.0% [1/105] in non-HCC, P=0.004); S210R (34.8% [8/23] in HCC vs 3.8% [4/105] in non-HCC, P <0.001); P203Q+S210R (17.4% [4/23] in HCC vs 0% [0/110] in non-HCC, P=0.001). Both mutations reside in trans-membrane C-terminal domain critical for HBsAg-secretion. In in-vitro experiments, P203Q, S210R and P203Q+S210R significantly reduced the ratio [secreted/intracellular HBsAg] compared to wt at each time-point analysed (P <0.05), supporting an impaired HBsAg-secretion. Furthermore, P203Q and P203Q+S210R increased the percentage of cells in S-phase compared to wt, indicating cell-cycle progression (P203Q:26±13%; P203Q+S210R:29±14%; wt:18%±9, P <0.01. Additionally, S210R increased the percentage of cells in G2/M-phase (26±8% for wt versus 33±6% for S210R, P <0.001). CONCLUSIONS: Specific mutations in HBsAg C-terminus significantly correlate with HBV-induced HCC. They hamper HBsAg-secretion and are associated with increased cellular proliferation, supporting their involvement in HCC-development. The identification of viral genetic markers associated with HCC is critical to identify patients at higher HCC-risk that may deserve intensive liver monitoring, and/or early anti-HBV therapy.

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