Mice lacking hepatocyte IKK beta (Ikk beta(Delta hep)) are defective in TNF alpha-activation of hepatocellular transcription factor NF-kappa B, and highly susceptible to hepatotoxicity. Following diethylnitrosamine (DEN) exposure, Ikk beta(Delta hep) mice develop more hepatocellular carcinoma (HCC) than control mice due partly to enhanced DEN-induced hepatocyte death. Here we show that Ikk beta(Delta hep) hepatocytes display growth advantages over normal hepatocytes consisting of precocious PCNA and cyclin D1 expression during liver regeneration (shortened hepatocyte G(0)-G(1) transitions), and enhanced recovery efficiency, cyclin D1 expression and cell proliferation after plating. Ex vivo deletion of Ikk beta also accelerates hepatocyte growth. Ikk beta(Delta hep) hepatocyte proliferative responses show heightened sensitivity to TGF alpha and TNF alpha, and heightened expression of fibronectin, collagens I/III, nidogen, beta-actin and integrin beta 1 mRNAs. These findings suggest that altered mitogen signaling and expression of extracellular matrix and its associated components underlie growth advantages. Increased HCC development in Ikk beta(Delta hep) mice may also be caused by growth advantages of surviving Ikk beta-deleted hepatocytes. (C) 2009 Elsevier Inc. All rights reserved.