Targeted deletion of hepatocyte Ikkβ confers growth advantages

Mice lacking hepatocyte IKKβ (IkkβΔhep) are defective in TNFα-activation of hepatocellular transcription factor NF-κB, and highly susceptible to hepatotoxicity. Following diethylnitrosamine (DEN) exposure, IkkβΔhep mice develop more hepatocellular carcinoma (HCC) than control mice due partly to enhanced DEN-induced hepatocyte death. Here we show that IkkβΔhep hepatocytes display growth advantages over normal hepatocytes consisting of precocious PCNA and cyclin D1 expression during liver regeneration (shortened hepatocyte G0→G1 transitions), and enhanced recovery efficiency, cyclin D1 expression and cell proliferation after plating. Ex vivo deletion of Ikkβ also accelerates hepatocyte growth. IkkβΔhep hepatocyte proliferative responses show heightened sensitivity to TGFα and TNFα, and heightened expression of fibronectin, collagens I/III, nidogen, β-actin and integrin β1 mRNAs. These findings suggest that altered mitogen signaling and expression of extracellular matrix and its associated components underlie growth advantages. Increased HCC development in IkkβΔhep mice may also be caused by growth advantages of surviving Ikkβ-deleted hepatocytes.