FASEB J. 2019 Apr;33(4):5112-5125.doi: 10.1096/fj.201801111RR.Epub 2019 Jan 17.

Long noncoding RNA AK089579 inhibits epithelial-to-mesenchymal transition of peritoneal mesothelial cells by competitively binding to microRNA-296-3p via DOK2 in peritoneal fibrosis

Xiu Wei Zhang  1 Lei Wang  2 Hong Ding  2 Affiliations

Abstract

Peritoneal fibrosis (PF) represents a well-recognized complication associated with continuous ambulatory peritoneal dialysis therapy, characterized by a reversible epithelial-to-mesenchymal transition (EMT) at the early stage. The aim of the current study was to investigate the effects linked with the long noncoding RNA (lncRNA) AK089579 on the EMT of peritoneal mesothelial cells (PMCs) as well as the associated regulatory mechanisms of AK089579 downstream of tyrosine kinase 2 (DOK2) and microRNA-296-3p (miR-296-3p). Enrichment analysis, gene intersection association analysis, and a gene-gene intersection network were initially constructed to ascertain whether AK089579 regulated the expression of DOK2 through the mediation of miR-296-3p via the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway in PF. After the PF mouse model had been constructed, the expression of the proteins associated with the JAK2/STAT3 signaling pathway and EMT and PMC migration and invasion were all determined accordingly. Based on the obtained results, AK089579 was determined to function as a competing endogenous RNA for miR-296-3p while acting to up-regulate the expression of DOK2, which is a target gene of miR-296-3p. AK089579 was detected to confer an inhibitory effect on the activation of the JAK2/STAT3 signaling pathway, whereby the migration and invasion of PMCs among the mice models were suppressed. Meanwhile, up-regulated miR-296-3p and down-regulated DOK2 produced contrasting effects when compared with the aforementioned findings. Treatment with wp10066, a JAK2/STAS3 signaling pathway inhibitor, was shown to reverse the effects exerted by up-regulated miR-296-3p. Taken together, the central findings of the current study present evidence highlighting the capability of the lncRNA AK089579 to bind competitively to miR-296-3p and indirectly enhance the expression of DOK2, which in turn suppresses the activation of the JAK2/STAT3 signaling pathway, whereby the EMT, migration, and invasion of PMCs was inhibited in PF.-Zhang, X. W., Wang, L., Ding, H. Long noncoding RNA AK089579 inhibits epithelial-to-mesenchymal transition of peritoneal mesothelial cells by competitively binding to microRNA-296-3p via DOK2 in peritoneal fibrosis.

Keywords: JAK2/STAT3 signaling pathway; ceRNA; peritoneal fibrosis.

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