Viruses (Apr 2021)
Genetic Determinants in a Critical Domain of NS5A Correlate with Hepatocellular Carcinoma in Cirrhotic Patients Infected with HCV Genotype 1b
- Mohammad Alkhatib,
- Velia Chiara Di Maio,
- Valentina De Murtas,
- Ennio Polilli,
- Martina Milana,
- Elisabetta Teti,
- Gianluca Fiorentino,
- Vincenza Calvaruso,
- Silvia Barbaliscia,
- Ada Bertoli,
- Rossana Scutari,
- Luca Carioti,
- Valeria Cento,
- Maria Mercedes Santoro,
- Alessandro Orro,
- Ivana Maida,
- Ilaria Lenci,
- Loredana Sarmati,
- Antonio Craxì,
- Caterina Pasquazzi,
- Giustino Parruti,
- Sergio Babudieri,
- Luciano Milanesi,
- Massimo Andreoni,
- Mario Angelico,
- Carlo Federico Perno,
- Francesca Ceccherini-Silberstein,
- Valentina Svicher,
- Romina Salpini,
- on behalf of HIRMA (Hepatocarcinoma Innovative Research MArkers) and Fondazione Vironet C (HCV Virology Italian Resistance
Affiliations
- Mohammad Alkhatib
- Department of Experimental Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy
- Velia Chiara Di Maio
- Department of Experimental Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy
- Valentina De Murtas
- Department of Clinical and Experimental Medicine, University of Sassari, 07100 Sassari, Italy
- Ennio Polilli
- Infectious Diseases Unit, Pescara General Hospital, 65124 Pescara, Italy
- Martina Milana
- Hepatology Unit, University Hospital of Rome “Tor Vergata”, 00133 Rome, Italy
- Elisabetta Teti
- Infectious Diseases Unit, University Hospital of Rome “Tor Vergata”, 00133 Rome, Italy
- Gianluca Fiorentino
- Infectious Diseases Unit, Sant’Andrea Hospital—“Sapienza” University, 00189 Rome, Italy
- Vincenza Calvaruso
- Gastroenterology, “P. Giaccone” University Hospital, 90127 Palermo, Italy
- Silvia Barbaliscia
- Department of Experimental Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy
- Ada Bertoli
- Department of Experimental Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy
- Rossana Scutari
- Department of Experimental Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy
- Luca Carioti
- Department of Experimental Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy
- Valeria Cento
- Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy
- Maria Mercedes Santoro
- Department of Experimental Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy
- Alessandro Orro
- ITB-CNR, Institute of Biomedical Technologies, National Research Council of Italy, 20090 Milan, Italy
- Ivana Maida
- Department of Clinical and Experimental Medicine, University of Sassari, 07100 Sassari, Italy
- Ilaria Lenci
- Hepatology Unit, University Hospital of Rome “Tor Vergata”, 00133 Rome, Italy
- Loredana Sarmati
- Infectious Diseases Unit, University Hospital of Rome “Tor Vergata”, 00133 Rome, Italy
- Antonio Craxì
- Gastroenterology, “P. Giaccone” University Hospital, 90127 Palermo, Italy
- Caterina Pasquazzi
- Infectious Diseases Unit, Sant’Andrea Hospital—“Sapienza” University, 00189 Rome, Italy
- Giustino Parruti
- Infectious Diseases Unit, Pescara General Hospital, 65124 Pescara, Italy
- Sergio Babudieri
- Department of Clinical and Experimental Medicine, University of Sassari, 07100 Sassari, Italy
- Luciano Milanesi
- ITB-CNR, Institute of Biomedical Technologies, National Research Council of Italy, 20090 Milan, Italy
- Massimo Andreoni
- Infectious Diseases Unit, University Hospital of Rome “Tor Vergata”, 00133 Rome, Italy
- Mario Angelico
- Hepatology Unit, University Hospital of Rome “Tor Vergata”, 00133 Rome, Italy
- Carlo Federico Perno
- Department of Diagnostic and Laboratory Medicine, IRCCS Bambino Gesu’, Pediatric Hospital, 60165 Rome, Italy
- Francesca Ceccherini-Silberstein
- Department of Experimental Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy
- Valentina Svicher
- Department of Experimental Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy
- Romina Salpini
- Department of Experimental Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy
- on behalf of HIRMA (Hepatocarcinoma Innovative Research MArkers) and Fondazione Vironet C (HCV Virology Italian Resistance
- DOI
- https://doi.org/10.3390/v13050743
- Journal volume & issue
-
Vol. 13,
no. 5
p. 743
Abstract
HCV is an important cause of hepatocellular carcinoma (HCC). HCV NS5A domain-1 interacts with cellular proteins inducing pro-oncogenic pathways. Thus, we explore genetic variations in NS5A domain-1 and their association with HCC, by analyzing 188 NS5A sequences from HCV genotype-1b infected DAA-naïve cirrhotic patients: 34 with HCC and 154 without HCC. Specific NS5A mutations significantly correlate with HCC: S3T (8.8% vs. 1.3%, p = 0.01), T122M (8.8% vs. 0.0%, p p p 1 of them independently correlates with HCC (OR (95%CI): 21.8 (5.7–82.3); p p = 0.02) and lower ALT (35 (30–71) vs. 83 (48–108) U/L, p = 0.004), suggesting a role in enhancing viral fitness without affecting necroinflammation. Notably, these mutations reside in NS5A regions known to interact with cellular proteins crucial for cell-cycle regulation (p53, p85-PIK3, and β-catenin), and introduce additional phosphorylation sites, a phenomenon known to ameliorate NS5A interaction with cellular proteins. Overall, these results provide a focus for further investigations on molecular bases of HCV-mediated oncogenesis. The role of theseNS5A domain-1 mutations in triggering pro-oncogenic stimuli that can persist also despite achievement of sustained virological response deserves further investigation.
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