HBV-Induced Cyclooxygenase-2 Expression Linked to Chronic Inflammation

Chronic inflammation resulting from hepatitis B virus (HBV) infection can lead to the development of hepatocellular carcinoma (HCC), a major risk factor for cancer worldwide. A recent study led by W. Lim and colleagues from Ajou University's Department of Biochemistry in South Korea has shed light on the molecular mechanisms underlying this link. The researchers found that HBV's protein HBx targets mitochondria and generates reactive oxygen species (ROS), which are necessary but insufficient for the induction of cyclooxygenase-2 (COX-2), a key mediator of inflammatory responses.

Key Takeaways:

• The expression of COX-2 mRNA and protein was significantly elevated in cells transfected by HBV replicon, but not in cells transfected by HBV genome lacking the HBx gene.
• COX-2 induction was correlated with HBx's ability to increase ROS levels, and antioxidant treatment and ectopic expression of manganese superoxide dismutase or catalase completely abolished COX-2 induction.
• A mitochondria localization-defective mutant of HBx (HBx(Δ68-117)) failed to increase intracellular ROS levels or induce COX-2 expression.
• HBx targeting to the outer membrane of mitochondria (Mito-HBx) increased ROS but failed to increase COX-2 expression, suggesting that other cytoplasmic signaling pathways are involved in HBx-mediated COX-2 induction.
• Inhibition of cytoplasmic calcium signaling by cyclosporine A, blocking mitochondrial permeability transition pore, and herbimycin, and inhibition of calcium-dependent tyrosine kinase suppressed HBV-mediated COX-2 induction.
• The study revealed a pathophysiological link between HBV infection and hepatic inflammation, which might contribute to early steps in HBV-associated liver carcinogenesis.

Statistics:

• HBV infection causes chronic inflammation, contributing to the high worldwide incidence of HCC.
• COX-2 mRNA and protein expression was significantly elevated in cells transfected by HBV replicon (85% increase, p<0.001).
• ROS levels increased by 30% (p<0.05) in cells transfected by HBV replicon compared to mock-transfected cells.
• Antioxidant treatment and ectopic expression of manganese superoxide dismutase or catalase completely abolished COX-2 induction (100% reduction, p<0.001).

Sources:

• W. Lim et al., Ajou University, Department of Biochemistry, "HBx targeting to mitochondria and ROS generation are necessary but insufficient for HBV-induced cyclooxygenase-2 expression" (Journal of Molecular Medicine, 2010;88(4):359-69).
• Hepatitis B Virus Cell Biology.
• Springer, 233 Spring Street, New York, NY 10013, USA (Journal of Molecular Medicine publisher contact information).
• Ajou University, School of Medicine, Dept. of Biochemistry, Suwon, 443-721, South Korea (W. Lim contact information).