scholarly journals Transcriptomic and Metabolomic Profiling Reveal the p53-Dependent Benzeneacetic Acid Attenuation of Silica-Induced Epithelial–Mesenchymal Transition in Human Bronchial Epithelial Cells

2020 ◽  
Author(s):  
Meiling Zhou ◽  
Zhao Ju ◽  
Jing Jin ◽  
Huiji Pan ◽  
Ping Ding ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Dependent Manner ◽  
Altered Expression ◽  
Bronchial Epithelial ◽  
Mesenchymal Transition ◽  
Silica Exposure ◽  
Biomarker Research ◽  
Benzeneacetic Acid

Abstract Background: Silica exposure underlies the development of silicosis, one of the most serious occupational hazards worldwide. We aimed to explore the interaction of the silica-induced epithelial–mesenchymal transition (EMT)-related transcripts with the cellular metabolism regulated by p53.Methods: We knocked out p53 using CRISPR/Cas9 in the human bronchial epithelial (HBE) cell line. The transcriptomic and metabolomic analyses and integrative omics were conducted using microarrays, GC-MS, and MetaboAnalyst, respectively. Results: Fifty-two mRNAs showed significantly altered expression in the HBE p53-KO cells post-silica exposure. A total of 42 metabolites were putatively involved in p53-dependent silica-mediated HBE cell dysfunction. Through integrated data analysis, we obtained five significant p53-dependent metabolic pathways including phenylalanine, glyoxylate, dicarboxylate, and linoleic acid metabolism, and the citrate cycle. Through metabolite screening, we further identified that benzeneacetic acid, a key regulation metabolite in the phenylalanine metabolic pathway, attenuated the silica-induced EMT in HBE cells ina p53-dependent manner. Interestingly, despite the extensive p53-related published literature, the clinical translation of these studies remains unsubstantial. Conclusions: Our study offers new insights into the molecular mechanisms by which epithelial cells respond to silica exposure and provide fresh perspective and direction for future clinical biomarker research and potential clinically sustainable and translatable role of p53.

scholarly journals Transcriptomic and metabolomic profiling reveal the p53-dependent benzeneacetic acid attenuation of silica‐induced epithelial–mesenchymal transition in human bronchial epithelial cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Zhao Ju ◽  
Jianlin Shao ◽  
Meiling Zhou ◽  
Jing Jin ◽  
Huiji Pan ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Dependent Manner ◽  
Altered Expression ◽  
Bronchial Epithelial ◽  
Mesenchymal Transition ◽  
Silica Exposure ◽  
Biomarker Research ◽  
Benzeneacetic Acid

Abstract Background Silica exposure underlies the development of silicosis, one of the most serious occupational hazards worldwide. We aimed to explore the interaction of the silica-induced epithelial–mesenchymal transition (EMT)-related transcripts with the cellular metabolism regulated by p53. Methods We knocked out p53 using CRISPR/Cas9 in the human bronchial epithelial (HBE) cell line. The transcriptomic and metabolomic analyses and integrative omics were conducted using microarrays, GC–MS, and MetaboAnalyst, respectively. Results Fifty-two mRNAs showed significantly altered expression in the HBE p53-KO cells post-silica exposure. A total of 42 metabolites were putatively involved in p53-dependent silica-mediated HBE cell dysfunction. Through integrated data analysis, we obtained five significant p53-dependent metabolic pathways including phenylalanine, glyoxylate, dicarboxylate, and linoleic acid metabolism, and the citrate cycle. Through metabolite screening, we further identified that benzeneacetic acid, a key regulation metabolite in the phenylalanine metabolic pathway, attenuated the silica-induced EMT in HBE cells in a p53-dependent manner. Interestingly, despite the extensive p53-related published literature, the clinical translation of these studies remains unsubstantial. Conclusions Our study offers new insights into the molecular mechanisms by which epithelial cells respond to silica exposure and provide fresh perspective and direction for future clinical biomarker research and potential clinically sustainable and translatable role of p53.

scholarly journals Ionizing radiation induces epithelial–mesenchymal transition in human bronchial epithelial cells

2020 ◽  
Vol 40 (8) ◽  
Author(s):  
Bo Tang ◽  
Yue Xi ◽  
Fengmei Cui ◽  
Jin Gao ◽  
Huiqin Chen ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Ionizing Radiation ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Bronchial Epithelial Cells ◽  
Human Bronchial Epithelial Cells ◽  
Migration Ability ◽  
Bronchial Epithelial ◽  
Mesenchymal Transition ◽  
Potential Biomarker

Abstract Objective: The present study aimed to analyze the mechanism by which long-term occupational exposure of workers to low-dose ionizing irradiation induces epithelial–mesenchymal transition (EMT) of the human bronchial epithelial cells using transcriptome profiling. Methods: RNA-seq transcriptomics was used to determine gene expression in blood samples from radiation-exposed workers followed by bioinformatics analysis. Normal bronchial epithelial cells (16HBE) were irradiated for different durations and subjected to immunofluorescence, Western blotting, scratch healing, and adhesion assays to detect the progression of EMT and its underlying molecular mechanisms. Results: Transcriptomics revealed that exposure to ionizing radiation led to changes in the expression of genes related to EMT, immune response, and migration. At increased cumulative doses, ionizing radiation-induced significant EMT, as evidenced by a gradual decrease in the expression of E-cadherin, increased vimentin, elevated migration ability, and decreased adhesion capability of 16HBE cells. The expression of fibronectin 1 (FN1) showed a gradual increase with the progression of EMT, and may be involved in EMT. Conclusion: Ionizing radiation induces EMT. FN1 may be involved in the progression of EMT and could serve as a potential biomarker for this process.

scholarly journals Pseudomonas aeruginosa secreted protein PA3611 promotes bronchial epithelial cells epithelial-mesenchymal transition through TGF-β1 inducing p38/miRNA/NF-κB pathway

2020 ◽  
Author(s):  
Lei Shu ◽  
Sixia Chen ◽  
Xiaolin Chen ◽  
Shaoqing Lin ◽  
Xingran Du ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Epithelial Cells ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Cell ◽  
Bronchial Epithelial Cells ◽  
Dependent Manner ◽  
Bronchial Epithelial ◽  
Mesenchymal Transition ◽  
Cell Markers ◽  
Tgf Β1

AbstractPseudomonas aeruginosa (PA) is one of the important pathogens, which has been proven to colonize and cause infection in the respiratory tract of patients with structural lung diseases, and further lead to bronchial fibrosis. Epithelial-Mesenchymal Transition (EMT) of bronchial epithelial cells plays a vital role in the process of bronchial fibrosis. Up to the present, the research on bronchial epithelial cells EMT caused by secreted virulence factors of PA has not been reported. In our present study, we found that PA3611 protein stimulation induced the bronchial epithelial cells EMT with up-regulation of mesenchymal cell markers and down-regulation of epithelial cell markers. Meantime, TGF-β1 secretion was markedly increased, IκBα expression was significantly decreased, and NF-κB p65 subunit phosphorylation was markedly enhanced, in addition, the levels of miR-3065-3p and miR-6802-3p expression and p38 MAPK phosphorylation were obviously increased in bronchial epithelial cells after PA3611 stimulation, further research revealed that PA3611 promoted EMT occur through TGF-β1 induced p38/miRNA/NF-κb pathway. The function of PA3611 was also verified in PA-infected rats and results showed that ΔPA3611 could reduce lung inflammation and EMT. Overall, our results revealed that PA3611 promotes EMT via simulating the production of TGF-β1 induced p38/miRNA/NF-κB pathway-dependent manner, suggesting that PA3611 acts as a crucial virulence factor in bronchial epithelial cells EMT process and has potential use as a target for clinical treatment of bronchial EMT and fibrosis caused by chronic PA infection.Author summaryStructural lung disease can increase the chance of chronic infection, including infected by Pseudomonas aeruginosa, which can cause lung structure damages and affect lung functions in further, and forming a vicious circle of intertwining, ultimately, it leads to pulmonary fibrosis. EMT of bronchial epithelial cells plays a vital role in the process of bronchial fibrosis. However, the relationship and mechanism of PA infection leads to the destruction of lung structure and bronchial epithelial cells EMT are still not very clear. We found pseudomonas aeruginosa secreted protein PA3611 can stimulate bronchial epithelial cells EMT through up-regulation of mesenchymal cell markers α-SMA and Vimentin expression and down-regulation of epithelial cell markers E-cadherin and Zonula Occludens-1. Meantime, TGF-β1 secretion was markedly increased, IκBα expression was significantly decreased, and NF-κB p65 subunit phosphorylation was markedly enhanced, in addition, the levels of miR-3065-3p and miR-6802-3p expression and p38 MAPK phosphorylation were obviously increased in bronchial epithelial cells after PA3611 stimulation, further studies suggested that PA3611 was shown to promote EMT occur through TGF-β1 induced p38/miRNA/NF-Kb pathway. Our results revealed that PA3611 promotes EMT via simulating the production of TGF-β1 induced p38/miRNA/NF-κB pathway-dependent manner, suggesting that PA3611 acts as a crucial virulence factor in bronchial epithelial cells EMT process and as a potential target for the treatment of chronic structural lung diseases.

scholarly journals LncRNA MALAT1, an lncRNA acting via the miR-204/ZEB1 pathway, mediates the EMT induced by organic extract of PM2.5 in lung bronchial epithelial cells

2019 ◽  
Vol 317 (1) ◽  
pp. L87-L98 ◽  
Author(s):  
Fei Luo ◽  
Hongying Wei ◽  
Huaqi Guo ◽  
Yan Li ◽  
Yan Feng ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Respiratory Health ◽  
Bronchial Epithelial Cells ◽  
Similar Response ◽  
Bronchial Epithelial ◽  
Mesenchymal Transition ◽  
Organic Extracts

Extensive cohort studies have explored the hazards of particulate matter with aerodynamic diameter 2.5 μm or smaller (PM2.5) to human respiratory health; however, the molecular mechanisms for PM2.5 carcinogenesis are poorly understood. Long non-coding RNAs (lncRNAs) are involved in various pathophysiological processes. In the present study, we investigated the effect of PM2.5 on the epithelial-mesenchymal transition (EMT) in lung bronchial epithelial cells and the underlying mechanisms mediated by an lncRNA. Organic extracts of PM2.5 from Shanghai were used to treat human bronchial epithelial cell lines (HBE and BEAS-2B). The PM2.5 organic extracts induced the EMT and cell transformation. High levels of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), mediated by NF-κB, were involved in the EMT process. For both cell lines, there was a similar response. In addition, MALAT1 interacted with miR-204 and reversed the inhibitory effect of its target gene, ZEB1, thereby contributing to the EMT and malignant transformation. In sum, these findings show that NF-κB transcriptionally regulates MALAT1, which, by binding with miR-204 and releasing ZEB1, promotes the EMT. These results offer an understanding of the regulatory network of the PM2.5-induced EMT that relates to the health risks associated with PM2.5.

scholarly journals Pseudomonas Aeruginosa Secreted Protein PA3611 Promotes Bronchial Epithelial Cells Epithelial-Mesenchymal Transition Through TGF-β1 Inducing p38/miRNA/NF-κB Pathway

2020 ◽  
Author(s):  
Lei Shu ◽  
Sixia Chen ◽  
Xiaolin Chen ◽  
Shaoqing Lin ◽  
Xingran Du ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Cell ◽  
Vital Role ◽  
Bronchial Epithelial Cells ◽  
Dependent Manner ◽  
Bronchial Epithelial ◽  
Mesenchymal Transition ◽  
Cell Markers ◽  
Tgf Β1

Abstract BackgroundPseudomonas aeruginosa (PA) is one of the important pathogens, which has been proven to colonize and cause infection in the respiratory tract of patients with structural lung diseases, and further lead to bronchial fibrosis. Epithelial-Mesenchymal Transition (EMT) of bronchial epithelial cells plays a vital role in the process of bronchial fibrosis. Up to the present, the research on bronchial epithelial cells EMT caused by secreted virulence factors of PA has not been reported. ResultsIn our present study, we found that PA3611 protein stimulation induced the bronchial epithelial cells EMT with up-regulation of mesenchymal cell markers and down-regulation of epithelial cell markers. Meantime, TGF-β1 secretion was markedly increased, IκBα expression was significantly decreased, and NF-κB p65 subunit phosphorylation was markedly enhanced, in addition, the levels of miR-3065-3p and miR-6802-3p expression and p38 MAPK phosphorylation were obviously increased in bronchial epithelial cells after PA3611 stimulation, furthermore, PA3611 was shown to promote EMT occur through TGF-β1 induced p38/miRNA/NF-Κb pathway. The function of PA3611 was also verified in PA-infected rats and results showed that △PA3611 could reduce lung inflammation and EMT. ConclusionsOverall, our results revealed that PA3611 promotes EMT via simulating the production of TGF-β1 induced p38/miRNA/NF-κB pathway-dependent manner, suggesting that PA3611 acts as a crucial virulence factor in bronchial epithelial cells EMT process and has potential use as a target for clinical treatment of bronchial EMT and fibrosis caused by chronic PA infection.

scholarly journals The Molecular Mechanism of Epithelial–Mesenchymal Transition for Breast Carcinogenesis

Biomolecules ◽  
2019 ◽  
Vol 9 (9) ◽  
pp. 476 ◽  
Author(s):  
Chia-Jung Li ◽  
Pei-Yi Chu ◽  
Giou-Teng Yiang ◽  
Meng-Yu Wu
Keyword(s):  
Epithelial Cells ◽  
Tumor Progression ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Transforming Growth Factor Β ◽  
Inhibition Of Proliferation ◽  
Mesenchymal Transition

The transforming growth factor-β (TGF-β) signaling pathway plays multiple regulatory roles in the tumorigenesis and development of cancer. TGF-β can inhibit the growth and proliferation of epithelial cells and induce apoptosis, thereby playing a role in inhibiting breast cancer. Therefore, the loss of response in epithelial cells that leads to the inhibition of cell proliferation due to TGF-β is a landmark event in tumorigenesis. As tumors progress, TGF-β can promote tumor cell invasion, metastasis, and drug resistance. At present, the above-mentioned role of TGF-β is related to the interaction of multiple signaling pathways in the cell, which can attenuate or abolish the inhibition of proliferation and apoptosis-promoting effects of TGF-β and enhance its promotion of tumor progression. This article focuses on the molecular mechanisms through which TGF-β interacts with multiple intracellular signaling pathways in tumor progression and the effects of these interactions on tumorigenesis.

scholarly journals Pathological Study on Epithelial-Mesenchymal Transition in Silicotic Lung Lesions in Rat

2019 ◽  
Vol 6 (3) ◽  
pp. 70 ◽  
Author(s):  
Mao Komai ◽  
Karin Mihira ◽  
Akinori Shimada ◽  
Ikumi Miyamoto ◽  
Kikumi Ogihara ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Pulmonary Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
Crystalline Silicon ◽  
Interstitial Fibrosis ◽  
Female Rats ◽  
Dependent Manner ◽  
Type Ii ◽  
Mesenchymal Transition ◽  
Spindle Cells

Silicosis, caused by the inhalation of crystalline silicon dioxide or silica, is one of the most severe occupational diseases. Persistent inflammation and progressive massive pulmonary fibrosis are the most common histological changes caused by silicosis. Association of epithelial-mesenchymal transition (EMT) of hyperplastic type II epithelial cells with the fibrotic events of pulmonary fibrosis has been suggested in in vitro silica-exposed cultured cell models, patients with idiopathic pulmonary fibrosis, and bleomycin-induced experimental models. Histological features of EMT, however, are not fully described in silicotic lungs in in vivo. The purpose of this study was to demonstrate EMT of hyperplastic type II epithelial cells in the developmental process of progressive massive pulmonary fibrosis in the lungs of rats exposed to silica. F344 female rats were intratracheally instilled with 20 mg of crystalline silica (Min-U-Sil-5), followed by sacrifice at 1, 3, 6, and 12 months after instillation. Fibrosis, characterized by the formation of silicotic nodules, progressive massive fibrosis, and diffuse interstitial fibrosis, was observed in the lungs of the treated rats; the effects of fibrosis intensified in a time-dependent manner. Hyperplasia of the type II epithelial cells, observed in the massive fibrotic lesions, dominated in the lungs of rats at 6 and 12 months after the treatment. Immunohistochemistry of the serial sections of the lung tissues demonstrated positive labeling for cytokeratin, vimentin, and α-smooth muscle actin in spindle cells close to the foci of hyperplasia of type II epithelial cells. Spindle cells, which exhibited features of both epithelial cells and fibroblasts, were also demonstrated with bundles of collagen fibers in the fibrotic lesions, using electron microscopy. Increased expression of TGF-β was shown by Western blotting and immunohistochemistry in the lungs of the treated rats. These findings suggested that enhanced TGF-β expression and EMT of hyperplastic type II epithelial cells are involved in the development process of progressive massive pulmonary fibrosis during silicosis.

Interleukin-27 Inhibits Epithelial-Mesenchymal Transition in Ovalbumin-Induced Mice Bronchial Epithelial Cells

2021 ◽  
Vol 11 (6) ◽  
pp. 1129-1137
Author(s):  
Yuanyuan Liu ◽  
Chao He ◽  
Xin Li ◽  
Zewen Zhang ◽  
Ju Liu ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Epithelial Mesenchymal Transition ◽  
Airway Remodeling ◽  
Bronchial Epithelial Cell ◽  
Phenotypic Marker ◽  
Bronchial Epithelial ◽  
Mesenchymal Transition ◽  
Stat3 Phosphorylation

The epithelial-mesenchymal transition (EMT) of bronchial epithelial cells is a critical mechanism involved in transforming growth factor beta 1 (TGF-β1) induced asthma airway remodeling. Previous study has shown that interleukin 27 (IL-27) attenuates EMT in alveolar epithelial cells, but its effects on the BEAS-2B human bronchial epithelial cell line EMT remain unknown. Herein, we explored the effects of IL-27 on BEAS-2B EMT in vivo and in vitro. In the in vivo experiments, we found that IL-27 nose-drip therapy alleviated airway remodeling, increased the epithelial phenotypic marker epithelial-cadherin (E-cadherin), and decreased the mesenchymal phenotypic marker alpha-smooth muscle actin (α-SMA) compared with the asthmatic control group. We also found that IL-27 suppressed the signal transducer and activator of transcription (STAT3) in the lung tissue of asthmatic mice. in vitro, TGF-β1-induced EMT changes, including downregulation of E-cadherin and upregulation of α-SMA, were suppressed by IL-27 treatment. Additionally, STAT3 phosphorylation was activated by TGF-β1, whereas IL-27 inhibited the activation of TGF-β1 induced STAT3 phosphorylation. Our findings indicated that IL-27 could inhibit airway remodeling by attenuating bronchial epithelial cell EMT in vivo and in vitro. Therefore, IL-27 may be a beneficial therapeutic option targeting asthmatic airway remodeling.

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