CccDNA– induced hepatocarcinogenesis is regulated by an HBx–stimulated interaction between male specific lethal 2 and cccDNA

Abstract

Introduction: Chronic hepatitis B virus is the leading cause of hepatocellular carcinoma (HCC).Covalently closed circular DNA (cccDNA) is an intermediate in the life cycle of HBV. HBV-encoded X protein (HBx), a key viral oncoprotein, can be specifically ubiquitylated by male specific lethal 2 (MSL2), which up-regulates its activity and promotes transcription, cell proliferation, and tumor growth. Method: We compared associations among cccDNA, MSL2mRNA, and HBxmRNA levels in tumor and peri-tumor tissues and clarified the effect of antiviral therapy on these indicators.Levels of intrahepatic cccDNA, MSL2mRNA, and HBxmRNA were compared in patients with HBV-related HCC who had undergone liver surgery by real-time PCR. Result: Fifty patients were included in this study. Before surgery, 31 had undergone antiviral treatment. Intrahepatic cccDNA levels were significantly higher in the tumor tissues than peri-tumor tissues (p= 0.001), especially in the HBeAg-positive (p= 0.008), tumor recurrence (p= 0.002), and < 3 cm tumor size (p= 0.003) groups. Levels of cccDNA and MSL2mRNA in the HBx-positive group were significantly higher in tumor tissues than peri-tumor tissues (p= 0.026 and 0.013). Levels of HBxmRNA in antiviral-treated tumor and peri-tumor tissues were significantly lower than those in untreated tissues (p= 0.026 and p= 0.035). Conclusion: In conclusion, cccDNA participated in the tumorigenesis of HBV-related HCC, a process possible regulated by an HBx-stimulated interaction between MSL2 and cccDNA. In addition, antiviral therapy could inhibit this process by reducing HBx levels.