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.
Cancer is caused by an accumulation of genetic lesions that cooperate to convert normal cells into cancer cells characterized by uncontrolled proliferation, survival, self-renewal capacity, and invasiveness. The tumor suppressor gene p53 and its downstream effectors such as mir-200 provide a crucial line of defense against tumor development by inducing cell cycle arrest or apoptosis and are silenced in many cancers. With a better understanding of the mechanism of mir-200 in B-lymphoma, cancer therapies may be thoughtfully designed to exploit mir-200 activity and increase the sensitivity of tumor cells to conventional treatments.
