A Transcriptional Regulatory Network Model Reveals miR-34a as a Potential Regulator of Proliferation in Cancer Cell Lines

Abstract

The genetic instability caused by the disruption of the mechanism of the DNA-damage response (DDR) has been linked to cancer development. One of the most important and studied mechanism of the DDR is the p53 pathway. This protein acts as a tumor suppressor. MDM2, MDM4 and PLK1 inhibit its proapoptotic activity by binding to its sequence-specific DNA-binding site. To model the interactions between the species with the purpose of finding key points in the regulation of proliferation in cancer cell lines, we propose a transcriptional regulatory network conformed by miRNAs, mARNs and transcription factors involved in the modulation of p53 tumor suppressor protein using Ordinary Differential Equations. Our results suggest miR-34a has a strong control in the regulation of MDM4 and its overexpression results in the decrease of the expression of this protein without significantly affecting the expression of p53. We propose that the combination of miR-34a and small molecule inhibitors of MDM2 may be a therapeutic alternative for treating cancer progression and relapse prevention.