Abstract #LB-63: Investigating the Requirement of NF-\#954;B Pathway Activation in MYC-Induced Liver Cancer

Abstract

Liver cancer is one of the most lethal forms of cancer with a 5-year survival rate of less than 5%. Hence, it is critical to identify pathways that may be essential for the genesis of liver cancer and can thus be targeted for therapeutic intervention. One such potential target is the nuclear factor-kappa B (NF-\#954;B) pathway. Recently, our laboratory developed a conditional transgenic murine model of MYC-induced liver cancer that is dependent upon the expression of this oncogene and regresses following its inactivation. In order to examine whether NF-\#954;B activation is essential for MYC-induced liver cancer, we established a transgenic system in which MYC can be activated in hepatocytes concomitantly with a mutant form of I\#954;B, thereby inhibiting the NF-\#954;B pathway. Excitingly, this approach has revealed that suppression of NF-\#954;B activation can significantly inhibit MYC-induced hepatocellular carcinoma in adult animals. Indeed, most animals remain tumor free even up to 8 months after oncogene activation compared to mortality in 100% of animals expressing only MYC within 6 months. Moreover, in the hosts that do develop liver tumors, there is evidence for activation of the NF-\#954;B, indicating a necessity for this pathway. Importantly, suppression of NF-\#954;B activation is not only similarly able to inhibit MYC-induced tumor formation in neonatal hosts, but animals that develop HCC in this context demonstrate a strikingly different tumor phenotype. Finally, analysis of tumor samples in which MYC has been inactivated reveals that there is a concomitant decrease in expression of NF-\#954;B target genes, suggesting a direct role of MYC in activation of NF-\#954;B in hepatocytes. Together, these data demonstrate that inhibition of the NF-\#954;B pathway is sufficient to abrogate MYC\#8217;s ability to induce tumorigenesis in the liver and thereby establish NF-\#954;B activation as an attractive therapeutic target for liver cancer.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-63.