A Lymphotoxin-Driven Pathway to Hepatocellular Carcinoma

Hepatitis B and C viruses (HBV and HCV) cause chronic hepatitis and hepatocellular carcinoma (HCC) by poorly understood mechanisms. We show that cytokines; lymphotoxin (LT) alpha and beta and their receptor (LTOR) are upregulated in HBV- or HCV-induced hepatitis and HCC. Liver-specific LT alpha beta expression in mice induces liver inflammation and HCC, causally linking hepatic LT overexpression to hepatitis and HCC. Development of HCC, composed in part of A6(+) oval cells, depends on lymphocytes and IKappa. B kinase beta expressed by hepatocytes but is independent of TNFR1. In vivo LT beta R stimulation implicates hepatocytes as the major LT-responsive liver cells, and LTOR inhibition in LT alpha beta-transgenic mice with hepatitis suppresses HCC formation. Thus, sustained LT signaling represents a pathway involved in hepatitis-induced HCC.