lncRNA PFAR Promotes Lung Fibroblast Activation and Fibrosis by Targeting miR-138 to Regulate the YAP1-Twist Axis

Abstract

Long non-coding RNAs (lncRNAs) have been reported to be involved in various pathophysiological processes in many diseases. However, the role and mechanism of lncRNAs in idiopathic pulmonary fibrosis (IPF) have not been explicitly delineated. In the present study, we reported that lncRNA NONMMUT065582, designated pulmonary fibrosis-associated RNA (PFAR), is upregulated in the lungs of mice with lung fibrosis as well as in fibrotic lung fibroblasts. Overexpression of PFAR promoted fibrogenesis through modulation of miR-138, whereas knockdown of PFAR attenuated TGF-β1-induced fibrogenesis in lung fibroblasts. In addition, knockdown of miR-138 promoted fibrogenesis by targeting regulation of yes-associated protein 1 (YAP1), whereas enhanced expression of miR-138 attenuated fibrogenesis in lung fibroblasts. Mechanistically, PFAR acted as competing endogenous RNA (ceRNA) of miR-138: forced expression of PFAR reduced the expression and activity of miR-138 to activate YAP1 and promote fibrogenesis in lung fibroblasts, whereas loss of YAP1 abrogated the pro-fibrotic effect of PFAR. More importantly, PFAR silencing alleviated BLM-induced lung fibrosis in mice. Taken together, the results of our study identified lncRNA PFAR as a new pro-fibrotic molecule that acts as a ceRNA of miR-138 during lung fibrosis and demonstrated PFAR as a novel therapeutic target for the prevention and treatment of lung fibrosis.

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.…”

Circular RNA hsa_circ_102209 promotes the growth and metastasis of colorectal cancer through miR-761-mediated Ras and Rab interactor 1 signaling

“…Previous studies have suggested that miRNAs were associated with the pathogenesis of cancer (20)(21)(22)(23)(24)(25). MiRNAs are promising oncogenic factor or tumor suppressors; they function as essential regulators of gene expression and are putative targets of circRNAs (19)(20)(21)(22)(23)(24). For instance, miR-93 is able to enhance the proliferation of glioma cells by targeting phosphatidylinositol 3 kinase/protein kinase B pathway (22).…”

“…MicroRNAs (miRNAs) are non-coding RNAs with the length of ~ 22 nt, which are potential downstream targets of other non-coding RNAs including lncRNAs and circRNAs (19,20). Previous reports have suggested that miRNAs exert their functions via binding to the 3' untranslated region of corresponding mRNAs (21,22).…”

Idiopathic Pulmonary Fibrosis: Pathogenesis and the Emerging Role of Long Non-Coding RNAs

“…Interestingly, the expression of lncRNA NONMMUT065582, also known as pulmonary fibrosis-associated RNA (PFAR), was found to be elevated in the fibrotic lungs of mice as well as mouse fibroblasts [138]. The LncRNA, PFAR, was shown to promote the development of fibrosis by acting as ceRNA for miR-138 and regulating the expression of yes-associated protein 1 (YAP1).…”