Tumorigenesis and Tumor Maintenance
Malignant transformation represents the endpoint of successive genetic lesions that confer uncontrolled proliferation and survival, unlimited replicative potential, and invasive growth. To date, most cancer research has focused on the alterations of protein coding genes, whereas the functions of non-coding RNAs (ncRNAs) in tumorigenesis remain largely unknown. Our research aims to identify and characterize novel ncRNAs that play essential roles during tumorigenesis and tumor maintenance. Particular efforts are focused on microRNAs (miRNAs), a novel class of small, ncRNAs that mediate post-transcriptional gene silencing (Fig.1). Using mouse tumor models and cell culture studies, we will elucidate the molecular basis of the miRNA functions in the oncogenic and tumor suppressor network, and explore the potential of miRNAs as diagnostic tools and/or therapeutic targets.
miRNAs encode a novel class of small, ncRNAs that regulate gene expression through post-transcriptional repression. Nascent miRNA transcripts are processed sequentially by two RNase III enzymes, Microprocessor and Dicer, to yield mature miRNA duplexes, ranging from 18bp to 24bp in length. One strand from the miRNA duplex, the mature miRNA, is then incorporated into the effector complex, RISC, which recognizes specific target mRNAs through imperfect base-pairing, and down-regulates their expression by post-transcriptional gene silencing. Occasionally, miRNAs are able to bind their target mRNAs with nearly perfect complementarity, and subsequently trigger the target cleavage through the RNA interference (RNAi) pathway. Emerging evidence has indicated the potential involvement of miRNAs in tumorigenesis, as certain miRNAs are subjected to changes in gene structure and expression regulation in human cancers. These observations have raised an intriguing hypothesis that certain miRNAs may be previously unrecognized components of the complex oncogenic and tumor suppressor networks.
A major current project is to characterize the mir17-92 miRNA cluster as a human oncogene in B-cell lymphoma. Using expression studies, we identified a miRNA cluster, mir17-92, whose expression is substantially increased in lymphomas and cancer-derived cell lines. Notably, the gene encoding mir17-92 is located within a genomic amplification found in diffuse large B-cell lymphomas and several other tumor types. To investigate if mir17-92 acts as an oncogene in mice, we tested the functional cooperation between mir17-92 and c-myc oncogene using the Eu-myc mouse B-cell lymphoma model (Fig2A). Enforced expression of mir17-92 greatly accelerates lymphoma-genesis in this model by repressing c-myc induced apoptosis (Fig2B). These findings indicate the functional importance of miRNAs during tumor formation, and implicate mir17-92 as a potential human oncogene. We are currently working to understand the molecular basis for the oncogenic effects of mir17-92.
A second major project is to characterize miRNA components of the p53 tumor suppressor pathway. As the guardian of the genome, the p53 pathway is activated in response to diverse cancer-related stress. The activation of p53 elicits multiple cellular processes that act collectively to prevent malignant transformation. To search for miRNA components in the tumor suppressor pathways, we compared miRNA expression profiles in cells carrying wild type p53 or mutated p53, and identified mir-34 family miRNAs as bona fide p53 transcriptional targets. mir-34s are induced by DNA damage and oncogene stress in a p53 dependent manner, and the mir-34 promoters contain canonical p53-binding elements that directly interact with p53. Our current studies aim to understand how mir-34s mediate the downstream effects of p53 to prevent malignant transformation.MacArthur Fellow, 2009-2014