Targeting the WntBeta-catenin Pathway in Liver Cancer

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DESCRIPTION (provided by applicant): Liver cancer is a leading cause of cancer mortality worldwide, frequently being associated with exposure to environmental toxins such as nitrosamines and aflatoxin. The molecular pathogenesis of this disease is not yet fully understood, thus limiting the ability to successfully treat or even prevent its development. One signaling pathway that has been implicated in hepatocarcinogenesis is the Wnt/(3-catenin pathway. Many mutations observed in liver tumor specimens in one way or another lead to aberrant activation of this pathway, including mutations in various serine and threonine residues which are important phosphorylation sites associated with the protein's proteasomal degradation. We hypothesize that such stabilization of 3- catenin provides the hepatocyte with a significant growth advantage during dysplastic growth conditions that result following toxin exposure. Furthermore, we believe that targeting this pathway pharmacologically can prevent and slow the development of liver cancer. To test this hypothesis we have developed a transgenic mouse line overexpressing (3-catenin mutated at Serine 45, one of the key phosphorylation sites for eventual degradation. In the first aim of this study, these mice will be exposed to diethylnitrosamine (DEN), a common hepatocarcinogen used in mice, to examine the development of liver cancer. We will also examine the potential of (3-catenin suppression in this model for chemoprevention and/or chemotherapy. In the second aim, we will explore activation of the facultative progenitor cells of the liver, oval cells, in Hep-S45D-TG mice given their potential role as cancer stem cells. Once again, we will utilize 3-catenin suppression to examine treatment potential for targeting this stem cell population. The identification of a key molecular player in liver cancer development and cancer stem cell activation could have a significant impact on therapy for patients who suffer from this high mortality disease. Liver cancer is a debilitating disease which is one of the leading causes of cancer death worldwide. The identification of a potential cause for this disease, aberrant 3-catenin activity, and the applicability of targeting this cause will have a significant impact on liver cancer therapy.