Down-regulation of USP13 mediates phenotype transformation of fibroblasts in idiopathic pulmonary fibrosis

Respiratory Research

Huaping Dai³  Chen Wang³  Dianhua Jiang¹  Jiurong Liang¹  Dingyuan Jiang²  Shuhong Li²  Xuefeng Xu⁴  Ying Li⁵  Xiaoxi Huang⁵  Jing Geng² 

[1] Department of Medicine Pulmonary Division and Women’s Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles 90048, CA, USA;Department of Respiratory and Critical Care Medicine, Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders, Beijing Chao-Yang Hospital-Beijing Institute of Respiratory Medicine, Capital Medical University, Beijing 100020, P.R. China;China–Japan Friendship Hospital, Beijing 100029, P.R. China;National Clinical Research Centre for Respiratory Medicine, Beijing Hospital, Beijing 100730, P.R. China;Department of Medical Research, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, P.R. China

关键词: Idiopathic pulmonary fibrosis;    PTEN;    Phenotype transformation;    Fibroblasts;    USP13;   

Others  :  1233501
DOI  :  10.1186/s12931-015-0286-3

 received in 2015-05-14, accepted in 2015-10-01,  发布年份 2015

【 摘 要 】

Background

Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by fibroblastic foci and progressive scarring of the pulmonary parenchyma. IPF fibroblasts display increased proliferation and enhanced migration and invasion, analogous to cancer cells. This transformation-like phenotype of fibroblasts plays an important role in the development of pulmonary fibrosis, but the mechanism for this is not well understood.

Methods

In this study, we compared gene expression profiles in fibrotic lung tissues from IPF patients and normal lung tissues from patients with primary spontaneous pneumothorax using a cDNA microarray to examine the mechanisms involved in the pathogenesis of IPF. In a cDNA microarray, we found that USP13 was decreased in lung tissues from patients with IPF, which was further confirmed by results from immunohistochemistry and western blot assays. Then, we used RNA interference in MRC-5 cells to inhibit USP13 and evaluated its effects by western blot, real-time RT-PCR, bromodeoxyuridine incorporation, and transwell assays. We also used co-immunoprecipitation and immunofluorescence staining to identify the correlation between USP13 and PTEN in IPF.

Results

USP13 expression levels were markedly reduced in fibroblastic foci and primary IPF fibroblast lines. The depletion of USP13 resulted in the transformation of fibroblasts into an aggressive phenotype with enhanced proliferative, migratory, and invasive capacities. Additionally, USP13 interacted with PTEN and mediated PTEN ubiquitination and degradation in lung fibroblasts.

Conclusions

Down-regulation of USP13 mediates PTEN protein loss and fibroblast phenotypic change, and thereby plays a crucial role in IPF pathogenesis.

【 授权许可】

   
2015 Geng et al.

【 图 表 】

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