The Tumor Suppressive Role of the mir-200 family of microRNAs

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DESCRIPTION (provided by applicant): p53 is considered the 'guardian of the genome' and consequently, loss of function of this essential tumor suppressor gene is one of the most common mutations in human cancer1-3. For this reason, extensive studies have focused on the upstream and downstream regulators and effectors of the p53 signaling pathway4-8. Recently, non-coding RNAs, in particular, microRNAs (miRNAs) have emerged as integral components in the tumor suppressor network. miRNAs are a novel class of non-coding RNAs that mediate post-transcriptional gene silencing of many mRNAs. One family of miRNAs, miR-200, consists of five members at two distinct genomic loci (miR-200b/a/429 and miR-200c/141) and plays an important role in p53-dependent tumor suppression in human breast and liver cancer. miR-200 suppresses important regulators for epithelial-mesenchymal transition (EMT), a process required for epithelial tumor cells to metastasize9-11. Surprisingly, my preliminary data also suggest a tumor suppressor role of miR- 200 in a B-cell lymphoma model, whose tumorigenesis is largely independent of EMT. miR-200 activity is down regulated in the E?-myc mouse model for Burkitt Lymphoma, and E?-myc/+; miR-200c/141-/- mice have an accelerated tumor onset. Here I propose to characterize the tumor suppressor functions of the miR-200 miRNAs in B-lymphoma using genetically engineered miR-200b/a/429 and miR-200c/141 knockout animals. Using mouse models and cell culture studies, I will also characterize the cellular and molecular pathways regulated by the p53-miR-200 axis, with particular focus on the role of miR-200 in proliferation, apoptosis, cell differentiation, and cell migration. Lastly I propose to identify th key miR- 200 targets that mediate these tumor suppression effects using a combined bioinformatic and experimental approach. The proposed studies will provide valuable information about the unique tumor suppressor mechanism of the p53-miR-200 axis in B cells, which could lead to the development of new diagnostic markers and therapeutic agents.