Non-protein-coding RNAs known as microRNAs (miRNAs or miRs) have recently been implicated as novel mediators of tumorigenesis. In fact, many human cancers are associated with defects in global miRNA biogenesis as well specific miRNA expression. For example, genomic amplifications of the miRNA polycistron known as miR-17-92 are associated with myc rearrangements in Burkitt's lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL), suggesting that these two lesions function cooperatively. Previously, our lab has demonstrated that the miR-17-92 cluster cooperates with the myc oncogene in the mouse model of Burkitt's Lymphoma known as E"mu"-myc. Furthermore, our lab has shown that miR-19 is the key oncogenic component in the cluster, both necessary and sufficient to promote myc-induced lymphomagenesis, inhibit the tumor suppressor PTEN, activate PI3K/AKT/mTOR signaling, and reduce c-myc induced apoptosis. Thus, identifying miRNA-mediated pathways that govern tumorigenesis are both critical for our understanding of cancer, and key to identifying therapeutic drug targets. In order to advance our understanding of the functions of miRNAs during tumorigenesis, this research strategy is composed of two aims: (1) characterize the role of the other miRNA components within miR-17-92 using tissue culture systems and animal models, and (2) identify genes repressed by components within miR-17-92 that control lymphomagenesis using in silico predictions and experimental validation. We hypothesize that other miRNAs in the miR-17-92 cluster may regulate the expression of genes that promote myc-induced lymphomagenesis. Due to the extensive association between miRNA dysregulation and cancer, the valuable insights we will gain through these studies will have a broad impact on global health.
MicroRNAs are a class of molecules that have recently been implicated as novel mediators of tumorigenesis. In this proposal, we characterize the individual contribution of each component which comprises the microRNA cluster known as miR-17-92. Due to the extensive association between miRNA dysregulation and cancer, the valuable insights we will gain through these studies have a broad impact on global health by elucidating the role of miRNAs in tumorigenesis and identifying miRNA-mediated pathways that as novel pharmacological targets against cancer.