Novel HBsAg mutations correlate with hepatocellular carcinoma, hamper HBsAg secretion and promote cell proliferation in vitro.
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Salpini Romina, Surdo Matteo, Warner Nadia, Cortese Maria Francesca, Colledge Danny, Soppe Sally, Bellocchi Maria Concetta, Armenia Daniele, Carioti Luca, Continenza Fabio, Di Carlo Domenico, 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
Аннотация
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.