Smad3‐mediated lncRNA HSALR1 enhances the non‐classic signalling pathway of TGF‐β1 in human bronchial fibroblasts by binding to HSP90AB1

Author:

Yi Erkang1ORCID,Lin Biting2,Zhang Yi2,Wang Xiaoyu1,Zhang Jiahuan1,Liu Yu1,Jin Jing1,Hong Wei2,Lin Zhiwei2,Cao Weitao1,Mei Xinyue1,Bai Ge1,Li Bing2ORCID,Zhou Yumin1ORCID,Ran Pixin13ORCID

Affiliation:

1. Guangzhou Institute of Respiratory Health & State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease & National Center for Respiratory Medicine The First Affiliated Hospital of Guangzhou Medical University Guangzhou Guangdong China

2. GMU‐GIBH Joint School of Life Sciences Guangzhou Medical University Guangzhou Guangdong China

3. Guangzhou Laboratory Bioland Guangzhou Guangdong China

Abstract

AbstractBackgroundChronic obstructive pulmonary disease (COPD) is one of the diseases with high mortality and morbidity with complex pathogenesis. Airway remodeling is an unavoidable pathological characteristic. However, the molecular mechanisms of airway remodeling are incompletely defined.MethodslncRNAs highly correlated with transforming growth factor beta 1(TGF–β1) expression were chosen, the lncRNA ENST00000440406 (named HSP90AB1 Assoicated LncRNA 1, HSALR1) was chosen for further functional experiments. Dual luciferase and ChIP assay were used to detect the upstream of HSALR1, transcriptome sequencing, Cck–8, Edu, cell proliferation, cell cycle assay, and WB detection of pathway levels confirmed the effect of HSALR1 on fibroblast proliferation and phosphorylation levels of related pathways. Mice was infected with adeno–associated virus (AAV) to express HSALR1 by intratracheal instillation under anesthesia and was exposure to cigarette smoke, then mouse lung function was performed and the pathological sections of lung tissues were analyzed.ResultsHerein, lncRNA HSALR1 was identified as highly correlated with the TGF–β1 and mainly expressed in human lung fibroblasts. HSALR1 was induced by Smad3 and promoted fibroblasts proliferation. Mechanistically, it could directly bind to HSP90AB1 protein, and acted as a scaffold to stabilize the binding between Akt and HSP90AB1 to promote Akt phosphorylation. In vivo, mice expressed HSALR1 by AAV was exposure to cigarette smoke (CS) for COPD modeling. We found that lung function was worse and airway remodeling was more pronounced in HSLAR1 mice compare to wild type (WT) mice.ConclusionOur results suggest that lncRNA HSALR1 binds to HSP90AB1 and Akt complex component, and enhances activity of the TGF–β1 smad3–independent pathway. This finding described here suggest that lncRNA can participate in COPD development, and HSLAR1 is a promising molecular target of COPD therapy.

Funder

National Natural Science Foundation of China

China Postdoctoral Science Foundation

Publisher

Wiley

Subject

Molecular Medicine,Medicine (miscellaneous)

Reference49 articles.

1. Chronic obstructive pulmonary disease (COPD). Accessed April 20 2018.http://www.who.int/news‐room/fact‐sheets/detail/chronic‐obstructive‐pulmonary‐disease‐(copd)

2. Biomass fuels are the probable risk factor for chronic obstructive pulmonary disease in rural South China

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