Identification and Characterization of Specific Genetic Elements in HBV Surface Glycoprotein correlated with Hepatocellular Carcinoma: An In Vivo and In Vitro Analysis

Valentina Svicher

An impairment in the secretion of HBV surface antigen (HBsAg) is known to promote the neoplastic transformation of the hepatocytes. Here, we investigated HBsAg genetic elements associated with HBV-induced hepatocellular carcinoma (HCC) and their impact on HBsAg secretion and cell proliferation. Thus, 133 HBV chronically infected patients: 23 with HCC, and 110 asymptomatic patients as control are analysed.
Two HBsAg mutations significantly correlate with HCC: P203Q (17.4% in HCC vs 0.8% in non-HCC, P=0.003), S210R (34.8% vs 3.6%, P<0.001), P203Q+S210R (17.4% vs 0%). They reside in transmembrane C-terminal domain critical for HBsAg secretion.
In vitro, the presence of P203Q, S210R and P203Q+S210R reduces the ratio of secreted/intracellular HBsAg compared to wt at each time point (3, 4 and 5 days post-trasfection, P<0.05, experiments in triplicate), supporting an impaired HBsAg secretion.
By flow cytometry, P203Q and the P203Q+S210R determine an increased % of cells in S-phase of cell cycle compared to wt (P<0.01), indicating cell cycle progression. Additionally, S210R determine an increased % of cells in G2/M-phase compared to wt (P<0.001).
In conclusion, key mutations, in C-terminal HBsAg domain, tightly correlate with HBV-related HCC. They affect HBsAg release and promote cell proliferation, supporting their involvement in HCC development. Their detection may help identifying patients at higher HCC risk that may deserve intensive liver monitoring, or early anti-HBV therapy

Anna Scotti
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