lncRNA PFAL promotes lung fibrosis through CTGF by competitively binding miR‐18a

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic parenchymal lung disease of unknown etiology and lacks an effective intervention. Long noncoding RNAs (lncRNAs) participate in organ fibrosis and various pulmonary diseases, but the role of lncRNAs in lung fibrosis is not fully understood. In the present study, we identified that lncRNA NONMMUT021928, designated as pulmonary fibrosis-associated lncRNA (PFAL), was up-regulated in the lungs of mice with experimental lung fibrosis, and in TGF-β1-induced fibrotic lung fibroblasts. Further study showed that overexpression of PFAL promoted cell proliferation, migration, and fibroblast-myofibroblast transition. Overexpression further resulted in extracellular matrix deposition and fibrogenesis in lung fibroblasts through regulation of microRNA-18a (miR-18a). Importantly, knockdown of PFAL alleviated lung fibrosis both in vitro and in vivo. Mechanistically, our study showed that PFAL promoted lung-fibroblast activation and fibrogenesis by acting as a competing endogenous RNA for miR-18a: forced expression of PFAL inhibited the expression and activity of miR-18a, whereas silencing of PFAL had the opposite effect. Furthermore, we found that miR-18a was decreased during lung fibrosis in vitro and in vivo, as well as in patients with IPF. Moreover, knockdown of miR-18a led to fibrogenesis in lung fibroblasts, whereas enhanced expression of miR-18a attenuated TGF-β1-induced lung fibrosis by directly targeting the regulation of connecting tissue growth factor. Taken together, these results revealed the effect and mechanism of lncRNA PFAL in pulmonary fibrosis and suggested that PFAL depletion may provide a novel strategy for the treatment of lung fibrosis.-Li, X., Yu, T., Shan, H., Jiang, H., Sun, J., Zhao, X., Su, W., Yang, L., Shan, H., Liang, H. lncRNA PFAL promotes lung fibrosis through CTGF by competitively binding miR-18a.

DROSHA-Dependent miRNA and AIM2 Inflammasome Activation in Idiopathic Pulmonary Fibrosis

“…Jiang et al showed that inhibition of pulmonary fibrosis-regulatory lncRNA (PFRL) prevents pulmonary fibrosis by disrupting the miR-26a/smad2 loop [34]. In addition, another lncRNA, pulmonary fibrosis-associated lncRNA (PFAL) was found to be upregulated during lung fibrosis in vitro and in vivo fibrosis models [35]. Mechanistically, PFRL promoted lung fibroblast activation by acting as a competing endogenous RNA for miR-18a.…”

Angelica Sinensis Polysaccharide Suppresses Epithelial-Mesenchymal Transition and Pulmonary Fibrosis via a DANCR/AUF-1/FOXO3 Regulatory Axis

“…Previous studies revealed that lncRNAs participate in various cellular processes and that the dysregulation of lncRNAs usually leads to the o development of diseases, such as cancer [14] and cardiovascular diseases [15]. Moreover, several studies indicated that certain lncRNAs, such as PFAR [16], lncITPF [17], PFRL [18] and PFAL [19], act as important regulators in the progression of IPF. However, the exact functions of lncRNAs in IPF remain elusive.…”

Decrypting the crosstalk of noncoding RNAs in the progression of IPF

“…The lncRNA, DNM3OS (dynamin 3 opposite strand) and its relevant miRNA, display differential expression in experimental or clinical conditions [72]. lncRNA NONMMUT021928, designated as a pulmonary fibrosis-associated lncRNA (PFAL), promotes cell propagation, migration, motility and fibroblast-myofibroblast transition processes by competitively binding to miR-18a [73]. The lnc-PCF accelerates the propagation of epithelial cells through the complementary binding of miR-344a-5p, which has the target gene map3k11 [74].…”

“…An exon circRNA with 1.2 kb, derived from the mammalian sex determination gene, may serve as a miR-138 sponge in the regulating process [57]. Furthermore, hsa_circRNA_100906 can bind to miR3245p/ miR3305p and hsa_circRNA_102348 can directly interact with miR630, both of which are downregulated in IPF [73]. Zhang et al [79] reported that miR3385p matches with hsa_circRNA_102101 and 102100 to regulate the coding gene CDC27, in IPF.…”

“…Hsa_circRNA_101996 can act as the molecular sponge of miR9 and 145, to regulate lung fibrosis via several signaling pathways, like the plateletderived growth factor receptor β (PDGFR-β) pathway [80,81]. Also, circRNA_ 102348 is upregulated and proves to directly interact with miR630 in IPF [73]. Is the sponge function of circRNAs a universal phenomenon?…”