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Abstract
p53 is a critical tumour suppressor gene at the centre of the cell’s innate tumour suppressive network. p53 function is eliminated via mutation in the majority of clinically detected human cancers and can otherwise be lost via aberrant regulation. We investigated whether microRNAs, non-coding RNAs that regulate genes in a post-transcriptional manner, may be involved in p53 regulation in cancer. We took a candidate-based approach to evaluating the function of microRNAs predicted to target p53. We found that overexpression of a single microRNA, miR 380 5p, could repress p53 levels. Conversely, knockdown of miR 380 5p induced p53 expression and a high level of apoptotic cell death. miR-380-5p was robustly expressed in human primary neuroblastoma, a childhood cancer of embryonic origin. This data is consistent with widespread expression of miR 380 5p in embryonic cells. Higher expression levels of miR 380-5p in a clinically relevant subset of neuroblastoma were associated with poor outcome, suggesting that miR-380-5p may be involved in the pathogenesis of neuroblastoma. Additional microRNAs clustered within the same imprinted domain on chromosome 14 as miR-380-5p were coexpressed with miR-380 5p in neuroblastoma. We identified a subset of human cancer cell lines from a range of tissues with appreciable expression of this cluster of microRNAs. Taken together, the work in this thesis suggests a novel mechanism of p53 functional attenuation via microRNAs. This work may have clinical implications for those cancers that retain wild-type p53, and are either derived from embryonic cells or recapitulate patterns of embryonic gene expression.