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

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    Author
    Salpini, R; Surdo, M; Warner, N; Cortese, MF; Colledge, D; Soppe, S; Bellocchi, MC; Armenia, D; Carioti, L; Continenza, F; ...
    Date
    2017-02-28
    Source Title
    Oncotarget
    Publisher
    IMPACT JOURNALS LLC
    University of Melbourne Author/s
    Locarnini, Stephen; Warner, Nadia
    Affiliation
    Microbiology and Immunology
    Infectious Diseases
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    Document Type
    Journal Article
    Citations
    Salpini, R., Surdo, M., Warner, N., Cortese, M. F., Colledge, D., Soppe, S., Bellocchi, M. C., Armenia, D., Carioti, L., Continenza, F., Di Carlo, D., Saccomandi, P., Mirabelli, C., Pollicita, M., Longo, R., Romano, S., Cappiello, G., Spano, A., Trimoulet, P. ,... Svicher, V. (2017). Novel HBsAg mutations correlate with hepatocellular carcinoma, hamper HBsAg secretion and promote cell proliferation in vitro. ONCOTARGET, 8 (9), pp.15704-15715. https://doi.org/10.18632/oncotarget.14944.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/259141
    DOI
    10.18632/oncotarget.14944
    Abstract
    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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