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

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 (IncRNA) 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 wpl0066, 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 IncRNA 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. FASEB J. 33, 5112–5125 (2019). http://www.fasebj.org

Comprehensive analysis of Downstream of Kinase (DOK) Genes in Pan-cancer

“…Another study found that DOK2 deletion is associated with mutations in EGFR in human lung adenocarcinoma, jointly promoting tumor development (19). In addition, DOK2 can be used as a poor prognostic marker for human glioblastoma multiforme and can inhibit tumor migration and invasion via the JAK2/STAT3 pathway (20,21). In our study, in addition to the signi cant survival correlation between DOK2 and lung adenocarcinoma, DOK1 and DOK6 were also signi cantly associated with lung adenocarcinoma.…”

LncRNA SNHG7 promotes cardiac remodeling by upregulating ROCK1 via sponging miR-34-5p

“…Increasing evidence have indicated lncRNAs' involvement in the pathogenesis of many diseases, including fibrosis [32][33][34]. Previous studies have showed that lncRNA PFAL contributed to the progression of pulmonary fibrosis [35].…”

Peritoneal fibrosis and epigenetic modulation

“…113 Zhang et al reported that lncRNA AK089579 had the ability to inhibit EMT, migration, and invasion of MCs, due to the competitive integration with miRNA-296-3p through DOK2 and JAK2/STAT3 signaling pathways. 78 Except for lncRNA AK089579, AV310809, uc007eib.1, AK142426, and ENSMUST00000053838 were upregulated in the fibrotic peritoneum, while others were demonstrated to be downregulated, such as uc007dlv.1, AK080622, BC049991, and uc008pwj.1. 94,110 This demonstrates close contact between lncRNAs and PF.…”

“…Through gene intersection association analysis, they found miR-296-3p can bind to lncRNA AK089579 competitively and upregulate the expression of target gene DOK2 consequently, thereby inhibiting PF by suppressing the activation of the JAK2/STAT3 signaling pathway. 78 Si et al developed a therapeutic strategy to target hyperglycolysis and fibrotic signaling during the development of PF induced by PDF in mice. They designed a triad of adeno-associated viruses that overexpressed miRNA-26a and miRNA-200a while inhibiting miRNA-21a.…”