Characterization and Validation of ceRNA-Mediated Pathway–Pathway Crosstalk Networks Across Eight Major Cardiovascular Diseases

Abstract

Pathway analysis is considered as an important strategy to reveal the underlying mechanisms of diseases. Pathways that are involved in crosstalk can regulate each other and co-regulate downstream biological processes. Furthermore, some genes in the pathways can function with other genes via the relationship of the competing endogenous RNA (ceRNA) mechanism, which has also been demonstrated to play key roles in cellular biology. However, the comprehensive analysis of ceRNA-mediated pathway crosstalk is lacking. Here, we constructed the landscape of the ceRNA-mediated pathway–pathway crosstalk of eight major cardiovascular diseases (CVDs) based on sequencing data from ∼2,800 samples. Some common features shared by numerous CVDs were uncovered. A fraction of the pathway–pathway crosstalk was conserved in multiple CVDs and a core pathway–pathway crosstalk network was identified, suggesting the similarity of pathway–pathway crosstalk among CVDs. Experimental evidence also demonstrated that the pathway crosstalk was functioned in CVDs. We split all hub pathways of each pathway–pathway crosstalk network into three categories, namely, common hubs, differential hubs, and specific hubs, which could highlight the common or specific biological mechanisms. Importantly, after a comparison analysis of the hub pathways of networks, ∼480 hub pathway-induced common modules were identified to exert functions in CVDs broadly. Moreover, we performed a random walk algorithm on the hub pathway-induced sub-network and identified 23 potentially novel CVD-related pathways. In summary, our study revealed the potential molecular regulatory mechanisms of ceRNA crosstalk in pathway–pathway crosstalk levels and provided a novel routine to investigate the pathway–pathway crosstalk in cardiology. All CVD pathway–pathway crosstalks are provided in http://www.licpathway.net/cepathway/index.html.