Lung fibrotic tenascin-C upregulation is associated with other extracellular matrix proteins and induced by TGFβ1

Estany, Susanna; Vicens-Zygmunt, Vanesa; Llatjós, Roger; Montes, Ana; Penín, R.M.; Escobar, Ignacio; Xaubet, Antoni; Santos, Salud; Manresa, F.; Dorca, Jordi; Molina-Molina, María

doi:10.1186/1471-2466-14-120

Cited by 85 publications

(78 citation statements)

References 29 publications

(42 reference statements)

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“…Increased deposition of VCAN has been demonstrated around active areas of fibrogenesis in the fibrotic lungs of patients with IPF (72). Increased expression of VCAN and enzymes essential for the synthesis and sulfation of associated GAGs was demonstrated in bleomycin-instilled rats and in fibrotic lung fibroblasts (88).…”

Section: Proteoglycansmentioning

confidence: 95%

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Matrix Remodeling in Pulmonary Fibrosis and Emphysema

Kulkarni

O’Reilly

Antony

et al. 2016

Am J Respir Cell Mol Biol

107

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Pulmonary fibrosis and emphysema are chronic lung diseases characterized by a progressive decline in lung function, resulting in significant morbidity and mortality. A hallmark of these diseases is recurrent or persistent alveolar epithelial injury, typically caused by common environmental exposures such as cigarette smoke. We propose that critical determinants of the outcome of the injury-repair processes that result in fibrosis versus emphysema are mesenchymal cell fate and associated extracellular matrix dynamics. In this review, we explore the concept that regulation of mesenchymal cells under the influence of soluble factors, in particular transforming growth factor-b1, and the extracellular matrix determine the divergent tissue remodeling responses seen in pulmonary fibrosis and emphysema.

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Section: Proteoglycansmentioning

confidence: 95%

“…ED-A-FN and TNC are present in abnormally larger quantities in fibrotic lung with increased synthesis of these glycoproteins by fibroblasts from patients with IPF compared with fibroblasts from normal subjects (41,72). They have been shown to colocalize with collagen and VCAN in fibroblastic foci, which are active sites of fibrogenesis (72).…”

Section: Elastinmentioning

confidence: 99%

Matrix Remodeling in Pulmonary Fibrosis and Emphysema

Kulkarni

O’Reilly

Antony

et al. 2016

Am J Respir Cell Mol Biol

107

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“…Tnc-knockout animals are protected against bleomycin-induced fibrosis and have lower accumulation of collagen, reduced fibroblast infiltration, and reduced activity of TGF-β in the lungs (18). Importantly, patients with pulmonary fibrosis show increased levels of Tnc, suggesting that the role of Tnc in pulmonary fibrosis is not limited to animal models of the disease (25,26). Whether Tnc contributes to the development and severity of the disease in humans, and what factors cause its up-regulation in that setting, remain open questions.…”

Section: Discussionmentioning

confidence: 99%

Quantitative proteomics identify Tenascin-C as a promoter of lung cancer progression and contributor to a signature prognostic of patient survival

Gocheva

Naba

Bhutkar

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

121

130

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The extracellular microenvironment is an integral component of normal and diseased tissues that is poorly understood owing to its complexity. To investigate the contribution of the microenvironment to lung fibrosis and adenocarcinoma progression, two pathologies characterized by excessive stromal expansion, we used mouse models to characterize the extracellular matrix (ECM) composition of normal lung, fibrotic lung, lung tumors, and metastases. Using quantitative proteomics, we identified and assayed the abundance of 113 ECM proteins, which revealed robust ECM protein signatures unique to fibrosis, primary tumors, or metastases. These analyses indicated significantly increased abundance of several S100 proteins, including Fibronectin and Tenascin-C (Tnc), in primary lung tumors and associated lymph node metastases compared with normal tissue. We further showed that Tnc expression is repressed by the transcription factor Nkx2-1, a well-established suppressor of metastatic progression. We found that increasing the levels of Tnc, via CRISPR-mediated transcriptional activation of the endogenous gene, enhanced the metastatic dissemination of lung adenocarcinoma cells. Interrogation of human cancer gene expression data revealed that high TNC expression correlates with worse prognosis for lung adenocarcinoma, and that a three-gene expression signature comprising TNC, S100A10, and S100A11 is a robust predictor of patient survival independent of age, sex, smoking history, and mutational load. Our findings suggest that the poorly understood ECM composition of the fibrotic and tumor microenvironment is an underexplored source of diagnostic markers and potential therapeutic targets for cancer patients.

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“…Idiopathic pulmonary fibrosis is characterized by excessive deposition of collagen, other ECM components, and excessive fibroblast proliferation. 30,31 Aschner et al 32 revealed that receptor-type protein tyrosine phosphatase a (PTP-a) promoted profibrotic signaling pathway in fibroblasts by modulating cellular responsiveness to TGF-b. Several studies have indicated that TGF-b could significantly increase the expression of collagen-1 and fibronectin.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-483-3p Inhibits Extracellular Matrix Production by Targeting Smad4 in Human Trabecular Meshwork Cells

Shen

Han

Huang

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. This study investigated the effects of microRNA-483-3p (miR-483-3p) on extracellular matrix (ECM) production, and clarified the regulatory mechanism of microRNA-483-3p in human trabecular meshwork cells (HTMCs) under oxidative stress. METHODS.The expression levels of ECM (fibronectin, laminin, collagen I) in HTMCs under oxidative stress were measured by Western blot. Changes of miR-483-3p expression in HTMCs were evaluated by quantitative polymerase chain reaction (qPCR). After using lentivirus stably expressing pri-miR-483, the effects of miR-483-3p on the ECM were assessed by qPCR and Western blot. Smad4, the potential target of miR-483-3p according to mRNA target-predicting algorithms, was confirmed by luciferase assay and Western blot. Furthermore, the effects of Smad4 knockdown on ECM expression were investigated by qPCR and Western blot.RESULTS. The mRNA and protein levels of ECM (fibronectin, laminin, collagen I) were upregulated in HTMCs induced by oxidative stress. The expression level of miR-483-3p decreased in HTMCs under oxidative stress, and the ectopic expression of miR-483-3p decreased the levels of ECM. In addition, miR-483-3p targeted Smad4 through two binding sites, resulting in a decrease of Smad4 expression. Furthermore, knockdown of Smad4 reduced the levels of ECM in HTMCs.CONCLUSIONS. MicroRNA-483-3p has an inhibitory effect on ECM production in HTMCs through downregulating Smad4, which indicates that miR-483-3p may serve as a potential therapeutic target in glaucoma.

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Lung fibrotic tenascin-C upregulation is associated with other extracellular matrix proteins and induced by TGFβ1

Cited by 85 publications

References 29 publications

Matrix Remodeling in Pulmonary Fibrosis and Emphysema

Matrix Remodeling in Pulmonary Fibrosis and Emphysema

Quantitative proteomics identify Tenascin-C as a promoter of lung cancer progression and contributor to a signature prognostic of patient survival

MicroRNA-483-3p Inhibits Extracellular Matrix Production by Targeting Smad4 in Human Trabecular Meshwork Cells

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