Excessive ROS accumulation promotes cell death through various mechanisms, including prolonged JNK activation. In support of this view, increased JNK phosphorylation and kinase activity are observed in livers of Ikk??hep mice ATPase signaling and DEN challenged Ikk?hep mice. Importantly, reduced hepatocyte death, less compensatory proliferation and suppressed hepatocarcinogenesis were observed upon crossing of Ikk?hep mice to Jnk1?/? mice. Therefore, the IKK/NF ?B pathway maintains hepatocyte survival by preventing ROS accumulation and excessive JNK activation, thereby reducing liver damage, proliferation and cancer development. In sharp contrast to the tumor suppressing role of hepatocyte IKK/NF ?B signaling in the mouse models described above, in other HCC models the NF ?B pathway was found to promote tumor development.
The first example came from the elegant work of Pikarsky and colleagues. They employed Mdr2 / mice, which spontaneously develop cholangitis due to defective cholesterol phospholipid secretion in the bile. These mice developed low grade BIRB 796 chronic liver inflammation that eventually results in the development of HCC. It was found that NF ?B was activated in Mdr2?/? hepatocytes, although the initial stimulus leading to NF ?B activation has not been fully identified. NF ?B activation promotes low amounts of TNF production and paracrine TNF signaling maintains NF ?B activation in Mdr2 / hepatocytes. Correspondingly, treatment of Mdr2 / mice with a neutralizing TNF antibody inhibits NF ?B activation in hepatocytes and decreases expression of NF ?B dependent anti apoptotic genes.
The authors examined the tumorigenic function of hepatocyte NF ?B by expressing a nondegradable form of I?B from a doxycycline regulated liver specific promoter and found that inhibition of NF ?B activation retarded and reduced HCC development in Mdr2 / mice. A similar tumorpromoting role for hepatocyte NF ?B was observed in transgenic mice that express lymphotoxin : heterotrimers in hepatocytes. LT: transgenic mice develop liver inflammation, evidenced by chronic penetration of T, B and dendritic cells into their livers and elevated production of cytokines such as IL 1, IFN? and IL 6. Chronic liver inflammation is accompanied by increased hepatocyte proliferation that eventually leads to appearance of HCC in old mice.
Crossing of LT: transgenic mice with Ikk?hep mice prevented liver inflammation and reduced HCC development, suggesting that in this case IKK activation in hepatocytes is tumor promoting because it is required to sustain the chronic inflammatory response initiated by LT: expression. Notably in both Mdr2 / and LT transgenic mice, HCC development depends on chronic low grade inflammation and no liver injury has been observed either prior to or subsequent to NF ?B inhibition. Thus in these models, in contrast to the injury driven Ikk?hepDEN and Ikk??hep models, the main function of NF ?B in hepatocytes appears to be the production of cytokines that maintain the inflammatory microenvironment in which these tumors develop. Figure 1 Roles of NF ?B signaling in hepatocarcinogenesis. In the injury promoted DEN hepatocarcinogenesis model, Kupffer cells are activated by IL 1 released from dying hepatocytes. Hepatocyte NF ?