Colorectal cancer (CRC) is the second leading cause of cancer related death in the United States. Although advanced diagnostic methods and therapeutic options significantly reduce death associated with this disease, recovery from stage III and IV of CRC remains very poor. This emphasizes the importance of investigation on the molecular mechanisms of CRC pathogenesis and identification of regulatory pathways, which can be targeted for therapeutic intervention. Genetic studies have identified several genes and pathways associated with CRC, among which most notably is the Wnt/b-catenin pathway. About 80% of CRC patients carry mutations in the Wnt/b-catenin pathway genes. Therefore, understandin...
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Colorectal cancer (CRC) is the second leading cause of cancer related death in the United States. Although advanced diagnostic methods and therapeutic options significantly reduce death associated with this disease, recovery from stage III and IV of CRC remains very poor. This emphasizes the importance of investigation on the molecular mechanisms of CRC pathogenesis and identification of regulatory pathways, which can be targeted for therapeutic intervention. Genetic studies have identified several genes and pathways associated with CRC, among which most notably is the Wnt/b-catenin pathway. About 80% of CRC patients carry mutations in the Wnt/b-catenin pathway genes. Therefore, understanding the regulatory mechanism of Wnt/b-catenin is critically important for the diagnosis, treatment, and management of CRC. In preliminary study, we identified an intracellular immune sensor named NLRP12 as a negative regulator of the Wnt/b-catenin pathway. Mice deficient in Nlrp12 are also highly susceptible to experimental CRC with higher tumor burden and rapid progression of CRC. However, the precise mechanism through which NLRP12 suppresses the Wnt/b-catenin pathway is unknown. Notably, NLRP12 also plays role in attenuating inflammatory responses independent of the Wnt/b-catenin pathway. This study therefore aims to define Wnt/b-catenin dependent and independent roles of NLRP12 in the protection against CRC. We will also study the molecular mechanism of NLRP12-mediated regulation of the Wnt/b-catenin pathway. Overall, this study will illustrate a novel pathway that regulates CRC induction and progression. Elucidation of the NLRP12-mediated regulation of the Wnt/b-catenin pathway will open opportunities for developing new therapeutic agents targeting NLRP12 or its associated signaling molecule involved in regulating the Wnt/b-catenin pathway.
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