The Role Of MicroRNA On Bistable Switch In A Cancer Network Involving MiR-17-92

MicroRNAs (miRNAs) are small, noncoding RNAs that play an important role in many key biological processes, including development, cell differentiation, the cell cycle and apoptosis, as central post-transcriptional regulators of gene expression. Recent studies have shown that miRNAs can act as oncogenes and tumor suppressors depending on the context.This thesis presents studies concerned with the effects of miRNA in the cancer network. First, in Chapter 1, we present a short recent research progress of miRNAs, including miRNA biogenesis, biological function of miRNA, and miRNA in human disease especially in human cancer. Then, a miniview on complex network is summarized in Chapter 2. We introduce some important parameters in networks, such as degree distribution, cluster, community, etc. and depict the basic mathematical descriptions of genetic regulation networks, Michaelis-Menteny equation and Hill equation.In Chapter 3, starting from an abstract model of the Myc/E2F/miR-17-92 network presented by Aguda et al. (2008), which is composed of coupling between the E2F/Myc positive feedback loops and the E2F/Myc/miR-17-92 negative feedback loop. We focuses on the physiological significance of miRNAs and their role in regulating the switching behavior. By systematically analyzing the network in close association with plausible experimental parameters, we show that, in the presence of miRNAs, the system bistability emerges from the system, with a bistable switch and a one-way switch presented by Aguda et al. instead of a single one-way switch. Moreover, the miRNAs can optimize the switching process. The model produces a diverse array of response-signal behaviors in response to various potential regulating scenarios. The model predicts that this transition exists, one from cell death or the cancerous phenotype directly to cell quiescence, due to the existence of miRNAs. It was also found that the network involving miR-17-92 exhibits high noise sensitivity due to a positive feedback loop and also maintains resistance to noise from a negative feedback loop.Finally, in Chapter 4, we summarize our recent results and outline the prospective of miRNA in cancer network. Because an individual miRNA usually targets many genes that are involved in various cellular signaling pathways, modulations in the level of a single miRNA could eventually affect many pathways at the same time. It would be worthwhile to construct a large-scale gene regulation network including different biological functions of a small group of miRNAs and to develop potential strategies of miRNA-based therapeutic targets.