Upregulation of Keratin 19 Expression by Hepatitis B Virus X Protein Promotes Hepatocellular Carcinoma Invasion, Metastasis, and Postoperative Recurrence

Abstract

Background: Chronic hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC). Objectives: To investigate the role of hepatitis B virus X protein (HBx) and keratin 19 (K19) in HCC invasion, migration, and recurrence Methods: Hepatocellular carcinoma cells were transfected with HBx and K19 genes to regulate their expression, and the effects of HBx and K19 on the biological functions of HCC cells were examined. Expression levels of HBx and K19 were also analysed in HCC tissues from 80 patients and correlated with clinicopathological factors, recurrence, metastasis, and survival time. Results: In vitro, HBx overexpression enhanced HCC cell migration, invasion, and tumoursphere formation by upregulating K19 expression. In the scratch test, cells transfected with HBx showed a higher wound-healing rate (P < 0.05), and invasion assays demonstrated increased invasive cells (P < 0.05). In patient HCC tissue samples, HBx and K19 positivity rates were 68.75% and 51.25%, respectively, with a strong positive correlation between their expression (r = 0.8333, P < 0.01). Both markers were associated with preoperative serum alpha-fetoprotein levels, HBV infection, tumour differentiation, vascular invasion, and tumour-node-metastasis stage (P < 0.05). Kaplan-Meier analysis showed worse 5-year overall survival and recurrence-free survival in patients with HBx-positive (OS 31% vs 48%; RFS 27% vs 48%; P = 0.0032) and K19-positive tumours (OS 29% vs 54%; RFS 46% vs 56%; P = 0.0002). Conclusions: The HBx protein promotes HCC invasion and metastasis by upregulating K19 expression. Both HBx and K19 expression levels may serve as potential biomarkers for evaluating postoperative efficacy and predicting prognosis in patients with HCC.