Comprehensive analysis of dysregulated exosomal long non-coding RNA networks associated with arteriovenous malformations

Abstract

Arteriovenous malformations (AVMs) are congenital vascular lesions with a high tendency for aggravation and recurrence after treatment, and their genesis remains enigmatic. In this study, we investigated exosomal long non-coding RNA (lncRNA) and mRNA expression and constructed a competitive endogenous RNA regulatory network in AVMs. Ethics approval was provided, and informed written consent was given prior to the inclusion of all participants. Blood samples were obtained from patients with AVMs and healthy controls at Shanghai Ninth People's Hospital, China, from May to November 2018, and total exosomes were isolated and validated. Differentially expressed exosomal lncRNAs and mRNAs were detected by RNA-seq, analysed by bioinformatic methods and validated by qRT-PCR. A competitive endogenous RNA regulatory network was constructed. The characteristics of the captured extracellular vesicles conformed to the features of exosomes. A total of 117 dysregulated exosomal lncRNAs and 1159 dysregulated exosomal mRNAs were identified in AVMs. qRT-PCR demonstrated that the exosomal lncRNAs MIR4435-1HG, LINC00657, LOC101927854 and SEPT5-GP1BB were upregulated in AVM exosomes. The Gene Ontology (GO) terms haemopoiesis and negative regulation of neuron projection development were significantly enriched in relation to dysregulated exosomal cis lncRNAs. A total of 199 GO terms and 80 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were enriched for the dysregulated exosomal mRNAs. In the exosomal lncRNA-miRNA-mRNA-related ceRNA regulatory network, the top 3 significant modules involved 31 dysregulated exosomal lncRNAs and 114 dysregulated exosomal mRNAs, which were enriched in the Rap 1, Ras, MAPK signalling pathways and platelet activation KEGG pathway. This study comprehensively identified dysregulated exosomal lncRNAs and mRNAs in AVMs, demonstrated the involvement of dysregulated lncRNA and mRNA patterns in AVMs and constructed an exosomal competitive endogenous RNA regulatory network.

Keywords: Competitive endogenous RNA; High-flow; Vascular anomalies.