The role of microRNAs in Oncogenesis and Stem Cell Identity.

摘要

With over 700 miRNA genes identified experimentally in the human genome and a plethora of computationally predicted mRNA targets, these small RNAs are thought to have a central role in diverse cellular and developmental processes. Aberrant expression of microRNAs (miRNAs) can lead to human diseases, including cancer. Several studies have confirmed that miRNAs regulate cellular functions such as cell proliferation and apoptosis. Furthermore, these non-coding RNAs can control cellular identity and mediate differentiation.;Understanding the mechanism of action of miRNAs in various biological contexts is critical in uncovering their exact roles in modulating gene expression. To study miRNAs we decided to use two systems as models in which we could explore miRNA function, Stem cells and Cancer. As a cancer model we used gliomas, the most common primary tumors in the central nervous system. Gliomas are complex tumors whose origin and progression are not understood well. They are thought to arise from oncogenically transformed multipotent Neural Stem Cells and thus provide an interesting model for the study of miRNAs both in cancer and stem cell biology. In addition to cancer as a model system, we used pluripotent human Embryonic Stem Cells as another model for understanding the role of miRNAs in stem cell maintenance and differentiation.;The findings of this research study determine the relationship between miRNA and mRNA target transcripts and their functional implications in cancer and stem cells. We demonstrate that miRNAs can control networks of genes involved in similar cellular processes. We were able to identify such networks by identifying both directly and non-directly regulated gene transcripts. We were able to determine indirect miRNA/mRNA interactions by identifying endogenous fluctuations in a set of mRNA and miRNA glioma tumor profiles. Furthermore, by studying miR-21, a miRNA that is highly expressed in glioma we determined the oncogenic mechanism of action miR-21, which directly targets a network of tumor suppressor in gliomas. Finally, with the use of stem cells we were able to demonstrate how two miRNAs, miR-145 and miR-128, target functionally related genes to control the balance between self-renewal (proliferation) and differentiation, thus control cell identity.