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

被引:74
|
作者
Zhao, Xiaoguang [1 ,2 ]
Sun, Jian [1 ,2 ]
Chen, Yingzhun [3 ]
Su, Wei [1 ,2 ]
Shan, Huitong [1 ,2 ]
Li, Yue [1 ,2 ]
Wang, Yining [1 ,2 ]
Zheng, Nan [1 ]
Shan, Hongli [1 ,2 ]
Liang, Haihai [1 ,2 ]
机构
[1] Harbin Med Univ, State Prov Key Labs Biomed Pharmaceut China, Key Lab Cardiovasc Res, Dept Pharmacol,Minist Educ,Coll Pharm, Baojian Rd 157, Harbin 150081, Heilongjiang, Peoples R China
[2] Harbin Med Univ, Heilongjiang Acad Med Sci, Northern Translat Med Res & Cooperat Ctr, Harbin 150081, Heilongjiang, Peoples R China
[3] Harbin Med Univ, Affiliated Hosp 2, Dept Pathol, Harbin, Heilongjiang, Peoples R China
基金
中国国家自然科学基金;
关键词
IDIOPATHIC PULMONARY-FIBROSIS; PROGRAMMED NECROSIS; NONCODING RNAS; INJURY; EMT; YAP;
D O I
10.1016/j.ymthe.2018.06.020
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
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-beta 1-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.
引用
收藏
页码:2206 / 2217
页数:12
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