Another Weapon in the Battle against Idiopathic Pulmonary Fibrosis?

Wilson, Carole L.; Hung, Chi F.

doi:10.1165/rcmb.2018-0387ed

Cited by 4 publications

(5 citation statements)

References 16 publications

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“…46 However, approaches targeting these cells thus far have been marred by specificity issues and adverse effects. 46,47 We, corroborated with other groups, have identified Met as a key molecule in IPF fibroblasts, 16,17 suggesting that it is an obvious target choice. However, Met inhibitors have had similar disadvantages as other drugs in their class.…”

Section: Discussionsupporting

confidence: 80%

“…13,18,45 In ASS1-deficient fibroblasts, we found that Met can mediate downstream Src and STAT3 signaling activity, driving an aggressive and anti-apoptotic phenotype. Although prior studies have already implicated Met in PF, 16,17 the trigger for its activation remains unclear. Herein, we have identified ASS1 as a regulator of Met activity and demonstrate a novel signal circuit: the ASS1-Met-Src-STAT3 signaling axis.…”

Section: Discussionmentioning

confidence: 95%

“…Of these RTKs, the Met receptor (HGFR) was the first to draw our attention, given recent reports showing the implications of Met activation in IPF. 16,17 To validate the regulation of the Met receptor and its downstream signaling by ASS1 expression, cell lysates from control and ASS1-knockdown normal fibroblasts were subjected to immunoblotting. An elevation of Met phosphorylation at Tyr1349, the multifunctional docking site, was observed in normal fibroblast cells with a lack of ASS1 (Figure 3D).…”

Section: Loss Of Ass1 Expression Activates Met Receptor and Its Downs...mentioning

confidence: 99%

“…15 The hepatocyte growth factor (HGF) receptor (HGFR, or Met), an oncogenic RTK, has been recently demonstrated to participate in driving profibrotic phenotypes and contributing to PF. 16,17 Activation of Met signaling initiates phosphatidylinositol 3-kinase (PI3K)/AKT, mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), Src/STAT3 cascades that control cell growth, invasion, and migration during oncogenesis. 18 Despite extensive studies of the Met pathway in a broad range of malignancies, how Met activity is regulated in fibroblasts and its functional consequence in PF remain to be established.…”

Section: Introductionmentioning

confidence: 99%

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Therapeutic targeting of argininosuccinate synthase 1 (ASS1)-deficient pulmonary fibrosis

Yang

Oldham

et al. 2021

Molecular Therapy

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 95%

Section: Loss Of Ass1 Expression Activates Met Receptor and Its Downs...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Therapeutic targeting of argininosuccinate synthase 1 (ASS1)-deficient pulmonary fibrosis

Yang

Oldham

et al. 2021

Molecular Therapy

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“…Another study has shown an increased MET expression in lung fibroblasts from patients with pulmonary fibrosis as compared with lung fibroblasts from normal people ( 32 ). Moreover, MET has been implicated in driving profibrotic phenotypes and leading to pulmonary fibrosis ( 33 , 34 ). Activation of lung fibroblast plays a major role in the pathogenesis of IPF ( 22 ).…”

Section: Discussionmentioning

confidence: 99%

Identification and validation of autophagy-related gene expression for predicting prognosis in patients with idiopathic pulmonary fibrosis

Huang

Xu²,

Chen³

et al. 2022

Front. Immunol.

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BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal fibrotic pulmonary disease with unknow etiology. Owing to lack of reliable prognostic biomarkers and effective treatment measures, patients with IPF usually exhibit poor prognosis. The aim of this study is to establish a risk score prognostic model for predicting the prognosis of patients with IPF based on autophagy-related genes.MethodsThe GSE70866 dataset was obtained from the gene expression omnibus (GEO) database. The autophagy-related genes were collected from the Molecular Signatures Database (MSigDB). Gene enrichment analysis for differentially expressed genes (DEGs) was performed to explore the function of DEGs. Univariate, least absolute shrinkage and selection operator (LASSO), as well as multivariate Cox regression analyses were conducted to identify a multi-gene prognostic model. Receiver operating characteristic (ROC) curve was applied to assess the prediction accuracy of the model. The expression of genes screened from the prognostic model was validated in clinical samples and human lung fibroblasts by qPCR and western blot assays.ResultsAmong the 514 autophagy-related genes, a total of 165 genes were identified as DEGs. These DEGs were enriched in autophagy-related processes and pathways. Based on the univariate, LASSO, and multivariate Cox regression analyses, two genes (MET and SH3BP4) were included for establishing the risk score prognostic model. According to the median value of the risk score, patients with IPF were stratified into high-risk and low-risk groups. Patients in high-risk group had shorter overall survival (OS) than low-risk group in both training and test cohorts. Multivariate regression analysis indicated that prognostic model can act as an independent prognostic indicator for IPF. ROC curve analysis confirmed the reliable predictive value of prognostic model. In the validation experiments, upregulated MET expression and downregulated SH3BP4 expression were observed in IPF lung tissues and TGF-β1-activated human lung fibroblasts, which is consistent with results from microarray data analysis.ConclusionThese findings indicated that the risk score prognostic model based on two autophagy-related genes can effectively predict the prognosis of patients with IPF.

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