Role of microRNAs in intestinal stem cell regulation and cancer initiation

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 DESCRIPTION (provided by applicant): Wnt/ß-catenin signaling is crucial for maintenance and activation of intestinal stem cells (ISCs). Mutations resulting in unregulated Wnt/ß-catenin have been linked to tumor initiation and growth. Recent evidence suggests that this pathway may also be a key mediator of the transition of ISCs to cancer stem cells (CSCs), which exhibit stem like features and contribute to metastasis and resistance to treatment. The underlying mechanisms by which canonical Wnt signaling mediates tumor formation are largely unknown, but emerging evidence suggests that deletion of APC or stabilization of ß-catenin results in aberrant expression of microRNAs (miRNAs). MiRNAs, a diverse class of highly conserved small non-coding RNAs (~22 nucleotides long), have been shown to play a critical role in cellular homeostasis and development and may also contribute to carcinogenesis. Whether miRNAs directly mediate the transformation of Lgr5+ ISCs has not been explored. To investigate the role of miRNAs in Wnt-mediated tumor formation, we performed global profiling of miRNA expression from intestinal crypts following stabilization of ß-catenin. Our analysis identified five miRNAs (let- 7e, miR-96, miR-223, miR-411 and miR-423-5p) that were differentially expressed and identified a general trend towards down-regulation of miRNAs, a phenomenon observed in human cancers. The following specific aims are designed to further investigate the role of miRNAs in the regulation of intestinal stem cells and the initiation of cancer. Aim 1. To investigate the role of specific miRNAs, identified by global crypt profiling, on ISC behavior. Aim 2. To determine the impact of global miRNA down-regulation on ISC behavior and adenoma formation. In summary, this proposal seeks to delineate the role of miRNAs and their targets on ISC behavior and adenoma formation. We anticipate that this could provide the basis for the development of novel Wnt-based biomarkers and therapeutics for intestinal cancer.