IKK/NF-κB system protects from Hepatitis B surface antigen-induced hepatocarcinogenesis

Background and aims: The NF-κB transcription factors are constitutively activated in many tumors, where they are thought to provide a critical survival signal for cancer cells. Accordingly, an inhibition of NF-κB signaling is considered a potential approach in anti-tumor therapy. We studied the oncogenic role NF-κB signaling in hepatocytes and immune cells using animals overexpressing hepatitis B virus surface antigen (HBsAg), an established model of virus-induced hepatocarcinogenesis.

Methods: HBsAg-overexpressing mice were crossed with animals overexpressing a dominant negative mutant of IKK2 (IKK2DN) under the control of tetracycline-inducible LAP-promotor (hepatocellular NF-κB inactivation) or with constitutive MyD88 knockouts (NF-κB inactivation predominantly in immune cells).

Results: When IKK2DN expression was activated at birth, the double-transgenic IKK2DN/HBsAg mice died perinatally. When the IKK2DN expression was activated at the age of 3 weeks, the double-transgenic animals developed a more pronounced hepatocellular carcinoma than the single HBsAg transgenes. Furthermore, the double transgenes displayed significantly higher extent of liver damage as indicated by transaminase levels. Similarly, double-transgenic MyD88-KO/HBsAg mice displayed both higher extent of liver damage and accelerated tumour development compared to the single HBsAg transgenes.

Conclusions: In HBsAg-overexpressing mice, NF-κB signaling in both hepatocytes and immune cells protects from hepatocarcinogenesis. As a potential mechanism, the loss of pro-survival NF-κB signaling likely leads to an increased cellular turnover and compensative hyperproliferation, which in turn accelerates the carcinogenesis.