Targeted deletion of hepatocyte Ikk{beta} confers growth advantages

Mice lacking hepatocyte IKK{beta} (Ikk{beta}{sup {delta}}{sup 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}{sup {delta}}{sup hep} mice develop more hepatocellular carcinoma (HCC) than control mice due partly to enhanced DEN-induced hepatocyte death. Here we show that Ikk{beta}{sup {delta}}{sup hep} hepatocytes display growth advantages over normal hepatocytes consisting of precocious PCNA and cyclin D1 expression during liver regeneration (shortened hepatocyte G{sub 0} {yields} G{sub 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}{sup {delta}}{sup 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}{sup {delta}}{sup hep} mice may also be caused by growth advantages of surviving Ikk{beta}-deleted hepatocytes.