Abstract
BackgroundIdiopathic 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.MethodsIn 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.ResultsUSP13 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.ConclusionsDown-regulation of USP13 mediates PTEN protein loss and fibroblast phenotypic change, and thereby plays a crucial role in IPF pathogenesis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-015-0286-3) contains supplementary material, which is available to authorized users.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a progressive lethal interstitial lung disease of unknown etiology with limited effective therapies [1]
Emerging evidence indicates that the abnormal behaviors of fibroblasts in IPF are associated with a variety of genetic alterations and the aberrant reactivation of developmental signaling pathways, such as hyaluronan synthase2 [13], focal adhesion kinase-related non-kinase [14], and phosphatase and tensin homologue deleted on chromosome 10 (PTEN) [15,16,17]
Decreased USP13 expression in tissues from IPF patients To identify gene expression profiles involved in the pathogenesis of IPF, we performed a comparative cDNA microarray analysis of the lung tissues from IPF patients (n = 5) and control subjects (n = 3)
Summary
Idiopathic pulmonary fibrosis (IPF) is a progressive lethal interstitial lung disease of unknown etiology with limited effective therapies [1]. It occurs more commonly in elderly adults, and the median survival time is only 2–3 years from diagnosis, similar to many cancers [1, 2]. 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
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