A novel lncRNA ABCE1-5 regulates pulmonary fibrosis by targeting KRT14.

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive and degenerative interstitial lung disease characterized by complex etiology, unclear pathogenesis, and high mortality. Long noncoding RNAs (lncRNAs) have been identified as key regulators in modulating the initiation, maintenance, and progression of pulmonary fibrosis. However, the precise pathological mechanisms through which lncRNAs are involved in IPF remain limited and require further elucidation. A novel lncABCE1-5 was identified as significantly decreased by an ncRNA microarray analysis in our eight IPF lung samples compared with three donor tissues and validated by quantitative real-time polymerase chain reaction (qRT-PCR) analysis in clinical lung samples. To investigate the biological function of ABCE1-5, we performed loss- and gain-of-function experiments in vitro and in vivo. LncABCE1-5 silencing promoted A549 cell migration and A549 and bronchial epithelial cell line (BEAS-2B) cell apoptosis while enhancing the expression of proteins associated with extracellular matrix deposition, whereas overexpression of ABCE1-5 partially attenuated transforming growth factor-beta (TGF-β)-induced fibrogenesis. Forced ABCE1-5 expression by intratracheal injection of adeno-associated virus 6 revealing the antifibrotic effect of ABCE1-5 in bleomycin (BLM)-treated mice. Mechanistically, RNA pull-down (RPD)-mass spectrometry and RNA immunoprecipitation assay demonstrated that ABCE1-5 directly binds to keratin14 (krt14) sequences, potentially impeding its expression by perturbing mRNA stability. Furthermore, decreased ABCE1-5 levels can promote krt14 expression and enhance the phosphorylation of both mTOR and Akt; overexpression of ABCE1-5 in BLM mouse lung tissue significantly attenuated the elevated levels of p-mTOR and p-AKT. Knockdown of krt14 reversed the activation of mTOR signaling mediated by ABCE1-5 silencing. Collectively, the downregulation of ABCE1-5 mediated krt14 activation, thereby activating mTOR/AKT signaling, to facilitate pulmonary fibrosis progression in IPF.NEW & NOTEWORTHY In the present study, our data first reveal that a novel lncRNA ABCE1-5 could inhibit pulmonary fibrosis through interacting with krt14 and negative regulation of its expression, and indicated ABCE1-5 also regulates the phosphorylation of mTOR and Akt, thus acting on extracellular matrix remodeling in lung fibrosis procession. These results suggest that novel molecules within the ABCE1-5-krt14-mTOR axis may serve as potential candidates for clinical application in IPF.