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Research Papers:

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

Romina Salpini, Matteo Surdo, Nadia Warner, Maria Francesca Cortese, Danny Colledge, Sally Soppe, Maria Concetta Bellocchi, Daniele Armenia, Luca Carioti, Fabio Continenza, Domenico Di Carlo, Patrizia Saccomandi, Carmen Mirabelli, Michela Pollicita, Roberta Longo, Sara Romano, Giuseppina Cappiello, Alberto Spanò, Pascale Trimoulet, Herve Fleury, Jacopo Vecchiet, Nerio Iapadre, Angelo Barlattani, Ada Bertoli, Terenzio Mari, Caterina Pasquazzi, Gabriele Missale, Cesare Sarrecchia, Elisa Orecchini, Alessandro Michienzi, Massimo Andreoni, Simona Francioso, Mario Angelico, Jens Verheyen, Francesca Ceccherini-Silberstein, Stephen Locarnini, Carlo Federico Perno _ and Valentina Svicher

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Oncotarget. 2017; 8:15704-15715. https://doi.org/10.18632/oncotarget.14944

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Abstract

Romina Salpini1,*, Matteo Surdo1,*, Nadia Warner2, Maria Francesca Cortese1, Danny Colledge2, Sally Soppe2, Maria Concetta Bellocchi1, Daniele Armenia1, Luca Carioti1, Fabio Continenza3, Domenico Di Carlo1, Patrizia Saccomandi1, Carmen Mirabelli1,4, Michela Pollicita1, Roberta Longo5, Sara Romano5, Giuseppina Cappiello5, Alberto Spanò5, Pascale Trimoulet6, Herve Fleury6, Jacopo Vecchiet7, Nerio Iapadre8, Angelo Barlattani9, Ada Bertoli1, Terenzio Mari10, Caterina Pasquazzi11, Gabriele Missale12, Cesare Sarrecchia13, Elisa Orecchini14, Alessandro Michienzi14, Massimo Andreoni13, Simona Francioso15, Mario Angelico15, Jens Verheyen16, Francesca Ceccherini-Silberstein1, Stephen Locarnini2, Carlo Federico Perno1, Valentina Svicher1

 1Department of Experimental Medicine and Surgery, University of Rome “Tor Vergata” Rome, Italy

 2Research and Molecular Development, Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria, Australia

 3Laboratory of Monitoring Antiviral Drugs, National Institute for Infectious Diseases (INMI) “Lazzaro Spallanzani” Rome, Italy

 4Institut Pasteur, Unité de Biologie des Virus Entériques, Paris, France

 5Unit of Microbiology, “S. Pertini Hospital”, Rome, Italy

 6Laboratoire de Microbiologie Fondamentale et Pathogénicité, Hôpital Pellegrin Tripode, Bordeaux, France

 7Department of Medicine and Aging Sciences, “SS Annunziata” Hospital, Chieti, Italy

 8Infectious Diseases Unit, “S Salvatore” Hospital, L'Aquila, Italy

 9Hepatology Unit, “S Giacomo” Hospital, Rome, Italy

10Hepatology Unit, “Regina Margherita” Hospital, Rome, Italy

11Hepato-Infectivology Unit, “S Andrea” Hospital, Rome, Italy

12Hospital of Parma, Parma, Italy

13Tor Vergata University Hospital, Infectious Diseases Unit, Rome, Italy

14Department of Biomedicine and Prevention, University of Rome “Tor Vergata” Rome, Italy

15Tor Vergata University Hospital, Hepatology Unit, Rome, Italy

16Institute of Virology, University Hospital, University of Duisburg-Essen, Essen, Germany

*These authors have contributed equally to this work

Correspondence to:

Carlo Federico Perno, email: [email protected]

Valentina Svicher, email: [email protected]

Keywords: hepatitis B, hepatocellular carcinoma, hepatitis B surface antigen, HBsAg mutations, cell proliferation

Received: November 25, 2016     Accepted: December 27, 2016     Published: February 01, 2017

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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