Dynamic and Modularized MicroRNA Regulation and Its Implication in Human Cancers

Abstract

MicroRNA is responsible for the fine-tuning of fundamental cellular activities and human disease development. The altered availability of microRNAs, target mRNAs, and other types of endogenous RNAs competing for microRNA interactions reflects the dynamic and conditional property of microRNA-mediated gene regulation that remains under-investigated. Here we propose a new integrative method to study this dynamic process by considering both competing and cooperative mechanisms and identifying functional modules where different microRNAs co-regulate the same functional process. Specifically, a new pipeline was built based on a meta-Lasso regression model and the proof-of-concept study was performed using a large-scale genomic dataset from ~4,200 patients with 9 cancer types. In the analysis, 10,726 microRNA-mRNA interactions were identified to be associated with a specific stage and/or type of cancer, which demonstrated the dynamic and conditional miRNA regulation during cancer progression. On the other hands, we detected 4,134 regulatory modules that exhibit high fidelity of microRNA function through selective microRNA-mRNA binding and modulation. For example, miR-18a-3p, −320a, −193b-3p, and −92b-3p co-regulate the glycolysis/gluconeogenesis and focal adhesion in cancers of kidney, liver, lung, and uterus. Furthermore, several new insights into dynamic microRNA regulation in cancers have been discovered in this study.

Integrated analysis of long noncoding RNA interactions reveals the potential role in progression of human papillary thyroid cancer

“…The summary results were identified to determine the specific interacted lncRNAs and mRNAs. Then, according to ceRNA theory, the negatively regulated lncRNA‐miRNA and mRNA‐miRNA pairs were analyzed in the ceRNA network in PTC . Finally, the ceRNA network was built using Cytoscape v3.0 .…”

“…Then, according to ceRNA theory, the negatively regulated lncRNA-miRNA and mRNA-miRNA pairs were analyzed in the ceRNA network in PTC. 27 Finally, the ceRNA network was built using Cytoscape v3.0. 28 The ceRNA network construction is illustrated in a flowchart ( Figure 2).…”

Combinatorial effect of miR-486-5p & miR-22-3p mimics thrombopoietin's impact on hematopoietic stem & progenitor cells

“…9,10 In these and other studies, a single EV miR was identified as responsible for the biological phenotype. There is increasing evidence however that two or more miRs are involved in co-regulating the same biological program or process in cancer 11,12 and normophysiology. 13 Combinations of miRs have been also used synthetically to regulate biological processes.…”

rSjP40 suppresses hepatic stellate cell activation by promoting microRNA‐155 expression and inhibiting STAT5 and FOXO3a expression

“…miRNAs can regulate gene expression at the post‐transcriptional level by degrading mRNA or inhibiting mRNA translation. miRNAs are involved in a series of important biological processes, such as cell proliferation, differentiation and apoptosis and play an important role in the physiological and pathological process . More and more studies have shown that miRNAs play an indispensable role in the progression of hepatic fibrosis.…”

“…miRNAs are involved in a series of important biological processes, such as cell proliferation, differentiation and apoptosis and play an important role in the physiological and pathological process. 15,16 More and more studies have shown that miRNAs play an indispensable role in the progression of hepatic fibrosis. For example, miR-145 inhibits the activation and proliferation of HSCs through regulating the Wnt/β-catenin signalling pathway.…”