TY  - JOUR
AU  - Salpini, R
AU  - Surdo, M
AU  - Warner, N
AU  - Cortese, MF
AU  - Colledge, D
AU  - Soppe, S
AU  - Bellocchi, MC
AU  - Armenia, D
AU  - Carioti, L
AU  - Continenza, F
AU  - Di Carlo, D
AU  - Saccomandi, P
AU  - Mirabelli, C
AU  - Pollicita, M
AU  - Longo, R
AU  - Romano, S
AU  - Cappiello, G
AU  - Spano, A
AU  - Trimoulet, P
AU  - Fleury, H
AU  - Vecchiet, J
AU  - Iapadre, N
AU  - Barlattani, A
AU  - Bertoli, A
AU  - Mari, T
AU  - Pasquazzi, C
AU  - Missale, G
AU  - Sarrecchia, C
AU  - Orecchini, E
AU  - Michienzi, A
AU  - Andreoni, M
AU  - Francioso, S
AU  - Angelico, M
AU  - Verheyen, J
AU  - Ceccherini-Silberstein, F
AU  - Locarnini, S
AU  - Perno, CF
AU  - Svicher, V
Y2  - 2021/02/04
Y1  - 2017/02/28
SN  - 1949-2553
UR  - http://hdl.handle.net/11343/259141
AB  - 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.
LA  - English
PB  - IMPACT JOURNALS LLC
T1  - Novel HBsAg mutations correlate with hepatocellular carcinoma, hamper HBsAg secretion and promote cell proliferation in vitro
DO  - 10.18632/oncotarget.14944
IS  - Oncotarget
VL  - 8
IS  - 9
SP  - 15704-15715
L1  - /bitstream/handle/11343/259141/PMC5362517.pdf?sequence=1&isAllowed=y
ER  -