MicroRNA regulation of molecular pathways as a generic mechanism and as a core disease phenotype

Abstract

The role of microRNAs as key regulators of a wide variety of fundamental cellular processes, such as apoptosis, differentiation, proliferation and cell cycle is increasingly recognized in most aspects of biology and biomedicine. Accretion of results from multiple microRNA studies over multiple pathway networks, led us to hypothesize that microRNAs target molecular pathways. As we show here, this is a network-wide phenomenon. The work presented, uses statistical tools that show how single microRNAs target molecular pathways. We demonstrate that this targeting could not be the result of random associations and cannot be the result of the sheer numeracy of microRNA targets. Furthermore, the strongest evidence for the association microRNA-pathway, is in a demonstration of the way by which these associations are disease-relevant. In our analyses we study ten different types of cancer involving thousands of samples, and show that the identified microRNA–pathway associations demonstrate a clinical affiliation and an ability to stratify patients. The work presented here shows the first evidence for a mechanism of microRNAs-pathway generic regulation. This regulation is tightly associated with clinical phenotype. The presented approach may catalyze targeted treatment through exposure of hidden regulatory mechanisms and a systems-medicine view of clinical observation.