Circular RNA Vav3 sponges gga-miR-375 to promote epithelial-mesenchymal transition

Abstract

Circular RNAs (circRNAs) are evolutionarily conserved and widely present, but their functions remain largely unknown. Recent development has highlighted the importance of circRNAs as the sponge of microRNA (miRNA) in cancer. We previously reported that gga-miR-375 was downregulated in the liver tumors of chickens infected with avian leukosis virus subgroup J (ALV-J) by microRNA microarray assay. It can be reasonably assumed in accordance with previous studies that the gga-miR-375 may be related to circRNAs. However, the question as to which circRNA acts as the sponge for gga-miR-375 remains to be answered. In this study, circRNA sequencing results revealed that a circRNA Vav3 termed circ-Vav3 was upregulated in the liver tumors of chickens infected with ALV-J. In addition, RNA immunoprecipitation (RIP), biotinylated RNA pull-down and RNA-fluorescence in situ hybridization (RNA-FISH) experiments were conducted to confirm that circ-Vav3 serves as the sponge of gga-miR-375. Furthermore, we confirmed through dual luciferase reporter assay that YAP1 is the target gene of gga-miR-375. The effect of the sponge function of circ-Vav3 on its downstream genes has been further verified by our conclusion that the sponge function of circ-Vav3 can abrogate gga-miR-375 target gene YAP1 and increase the expression level of YAP1. We further confirmed that the circ-Vav3/gga-miR-375/YAP1 axis induces epithelial-mesenchymal transition (EMT) through influencing EMT markers to promote tumorigenesis. Finally, clinical ALV-J-induced tumor livers were collected to detect core gene expression levels to provide a proof to the concluded tumorigenic mechanism. Together, our results suggest that circ-Vav3/gga-miR-375/YAP1 axis is another regulator of tumorigenesis.

circ_2858 Helps Blood-Brain Barrier Disruption by Increasing VEGFA via Sponging miR-93-5p during Escherichia coli Meningitis

“… 14 , 15 , 16 , 17 For example, circ-Vav3 was shown to be associated with epithelial-mesenchymal transition, whereas circHIPK3 is involved in cell growth. 18 , 19 Moreover, some studies have disclosed different working mechanisms of circRNAs, which can act as miRNA sponges, regulators of transcription and splicing, protein-protein interaction adapters, ribosomal RNA processing factors, etc. 20 , 21 , 22 , 23 Noticeably, our previous whole-transcriptome sequencing and transcriptome-wide bioinformatic analyses suggested a novel significantly upregulated circRNA, circ_2858, acting as a sponge for multiple members of the miR-17 family, which has been studied for its role in multiple infectious diseases.…”

Genome-wide profiling of host-encoded circular RNAs highlights their potential role during the Japanese encephalitis virus-induced neuroinflammatory response

“…Anomalous regulation of circRNAs has also been associated with a variety of pathologies, especially cancers and autoimmunity [12,13]. Moreover, recent RNA-seq studies showed that the expression of a large number of circRNAs undergoes alteration during the replication of the herpes virus, human immunodeficiency virus, and avian leukosis virus [13][14][15]. Notably, circRNAs carry conserved sequence motifs that are a complement to the sequences of microRNAs (miRNAs), thus, they can alter the activity of miRNAs by acting as miRNA-sponges [16].…”

Epigenetic Regulation by Non-Coding RNAs in the Avian Immune System

“…Several studies have been focused on the expression profile and the molecular regulatory mechanisms of circRNAs during the infection of ALV. Thousands of circRNAs were identified in various types of ALV-infected organs, and the number of differentially expressed circRNAs (DEcircRNAs) are calculated, ranges from dozens to thousands [49][50][51][52]. Gene ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the DEcircRNAs were involved in immune-related GO items and KEGG pathways.…”

“…Main GO terms include regulation of B-cell activation [49], B-cell differentiation [49,50], alpha-beta T-cell activation [49], and main KEGG pathways have signaling pathways of mTOR [49,50], TGF-beta [50], Toll-like receptor [50], RIG-I-like receptor [50], Jak-STAT [50], Insulin [50] and ErbB [50], MAPK [52], Wnt [52], and B-cell receptor [52]. Many circRNA-miRNA-mRNA ceRNA networks were characterized [49][50][51][52]. Even through so many circRNAs were identified, only few circRNAs were validated for their localization or functional mechanism.…”

“…circ-Vav3 can interact with miR-375 and upregulate the expression of yes-associated protein 1 (YAP1), a target gene of miR-375. circ-Vav3/miR-375/YAP1 axis participated in tumorigenesis through activating epithelial-mesenchymal transition (EMT) by altering the expression of EMT markers, including Vimentin, zinc finger E-box binding homeobox 1 (ZEB1), matrix metallopeptidase 2 (MMP2), N-cadherin, Fibronectin, and E-cadherin [51].…”