Decoding a Tumor-suppressive Gatekeeper Function of Pro-oncogenic Ras/MAPK and NF-κB Pathways in the Liver

Despite ever-rising mortality due to hepatocellular carcinoma (HCC), efforts to identify effective chemotherapeutics have languished. A major source of this difficulty may be the underappreciated complexity of oncogenic signaling mechanisms that drive liver tumorigenesis. The Ras/ERK and NF-κB pathways have received extensive attention in the cell signaling and cancer research fields in the past few decades. These pathways play critical roles in cell survival and proliferation, and have been demonstrated to drive oncogenesis when excessively or constitutively activated. However, studies in animal models have revealed tumor-suppressive functions in the liver, as deleting Shp2 or Ikkβ in hepatocytes, which promote Ras/ERK and NF-κB signaling, respectively, ironically aggravated HCC development induced by the chemical carcinogen diethylnitrosamine (DEN). Since parallel pathways might work antagonistically or cooperatively, our lab has been interested in taking a genetic approach to generate compound mutant mouse lines, which often yield unanticipated results and provide a fresh view on pathway cross-talk. The goal of my dissertation work was to dissect molecular and cellular mechanisms of hepatocarcinogenesis by creating a mutant mouse model with both Shp2 and Ikkβ deleted in hepatocytes. This allowed us to examine the functional interaction of these pathways in stressed and unstressed livers. My experimental results showed that dual Shp2 and Ikkβ deletion (DKO) dramatically accelerated DEN-induced tumorigenesis in the liver compared to either single knockout, evidently due to more extensive liver damages and metabolic disorders. More surprisingly, this dual deletion resulted in spontaneous development of HCC. Although multiple hepatic factors contributed to the pathogenic process, Shp2- and Ikkβ- deficient hepatocytes were characterized by disrupted expression of circadian clock genes. Circadian disruption has been linked to liver tumorigenesis in humans and in mice, suggesting a mechanism underlying spontaneous hepatocarcinogenesis in the DKO livers. In support of this mechanism, human HCCs with dysregulated circadian gene expression displayed downregulation of Ras/ERK and NF-κB signaling and poor prognosis. These data indicate that the ground state of the two central signaling pathways, previously known to mediate proliferative and oncogenic signaling, sustains tumor suppressive circadian homeostasis in the mammalian liver. Disruption of this signaling network results in spontaneous hepatocarcinogenesis