Modeling the role of microRNA-449a in the regulation of the G2/M cell cycle checkpoint in prostate LNCaP cells under ionizing radiation

Recent studies showed that induced microRNA-449a (miR-449a) enhances a G2/M cell cycle checkpoint arrest in prostate cancer (LNCaP) and lung adenocarcinoma cell lines. In the case of LNCaP cells, upregulated miR-449a directly downregulates c-Myc that is required to induce the cell cycle regulators Cdc25A and Cdc2/CyclinB whose inactivation blocks G2 to M phase transition. However, the molecular mechanisms involved are yet unclear, although in other prostate cancer cells the interactions among p53, miR-449a and Sirt-1 can affect the induction of the G2/M arrest. In order to clarify these molecular mechanisms, in this work we propose a boolean model of the G2/M checkpoint arrest regulation contemplating the influence of miR-449a. The model shows that the cell fate determination between two cellular phenotypes: G2/M-Arrest for DNA repair and G2/M-induced apoptosis is stochastic and influenced by miR-449a state of activation. The results were compared with experimental data available presenting agreement. We also found that several feedback loops are involved in this cell fate regulation and we indicate, through in silico gain or loss of function perturbations of genes, which of these feedback loops are more efficient to favor a specific phenotype.