Agonist of PPAR-γ Reduced Epithelial-Mesenchymal Transition in Eosinophilic Chronic Rhinosinusitis with Nasal Polyps via Inhibition of High Mobility Group Box1

Yang, Pingli; Chen, Shan; Zhong, Gang; Kong, Weijia; Wang, Yanjun

doi:10.7150/ijms.35936

Cited by 23 publications

(19 citation statements)

References 63 publications

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“…PPAR-γ exerted a negative feedback on SNA upregulated mesenchymal gene PPAR-γ was well known to suppress EMT [31][32][33][34] and inhibit metastases of HCC [35]. PPAR-γ can also affect transcription of mesenchymal genes known to be suppressed by SNA.…”

Section: Sna Directly Upregulated Transcription Of Fn and Lef In Tumomentioning

confidence: 99%

Snail upregulates FN and LEF transcription negatively feed backed by PPAR-gamma: a general model established for Snail to transactivate mesenchymal genes

Chen

Lee

et al. 2021

Preprint

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Background Snail (SNA) is responsible for epithelial mesenchymal transition, migration and metastasis of hepatocellular carcinoma. SNA represses the transcription of the essential epithelial marker such as E-cadherin and enhances mesenchymal markers including fibronectin and lymphoid enhancer-binding factor. Our previous studies indicated that SNA, in collaboration with EGR1 and SP1, may directly activate transcription of the mesenchymal markers, matrix degradation enzyme matrix metalloproteinases (MMP9) and zinc finger E-box binding homeobox 1 (ZEB1) in HepG2 cell stimulated by the phorbol ester tumor promoter 12-O-tetradecanoyl-phorbol 13-acetate (TPA). Besides, we pinpointed a SNA binding motif (TCACA) upstream of EGR1/SP1 overlapping region on promoters. In this study, we investigated whether LEF and FN are transcriptionally regulated by SNA in a similar fashion. Moreover, a general model for SNA-upregulated mesenchymal markers is proposed.Methods RT/PCR and Western blot were used for analyzing gene expression and shRNA technology for depleting SNA. Dual luciferase assay was used for promoter activation; deletion mapping and mutagenesis were used for confirming the indicated promoter region required for transcription activation. ChIP and EMSA were used for validating the binding of the indicated transcription factor on their putative motifs. Results SNA binding motif and E/S overlapping region are required for TPA-induced transcription of LEF and FN. These were supported by TPA-induced binding of SNA and EGR-1/SP-1 on indicated promoter regions. Moreover, a peroxisome proliferator-activated receptor γ motif upstream of SNA binding motif was found to be a negatively regulatory region in TPA-induced promoter activation of FN, LEF, MMP9 and ZEB1. This was supported by that co-treatment of a PPAR-g inhibitor, GW9662, and mutation of PPAR-g binding motif enhanced TPA-induced promoter activity and expression of the aforementioned genes whereas overexpression of PPAR-g reversed it. Moreover, comprehensive screening of the SNA-upregulated mesenchymal genes revealed similar sequence architecture on the promoter regions of the candidate genes: SNA binding motif (TCACA) coupled with a downstream EGR/SP1 overlapping region and an upstream PPAR-g binding motif. Among them COX2 and COL1A1 were found to potentially exhibit the same transcription mechanisms described above. Conclusions We established a general model for SNA-upregulated mesenchymal gene expressions negatively feed backed by PPAR-g.

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Section: Sna Directly Upregulated Transcription Of Fn and Lef In Tumomentioning

confidence: 99%

Snail upregulates FN and LEF transcription negatively feed backed by PPAR-gamma: a general model established for Snail to transactivate mesenchymal genes

Chen

Lee

et al. 2021

Preprint

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“…PPAR-γ belongs to a superfamily of nuclear hormone receptors and has the function of modulating lipid/lipoprotein metabolism, cell cycle progression, cellular proliferation, and differentiation after binding to ligand, and has been described to be involved in EMT in CRSwNP. It has been shown that the PPAR-γ agonist rosiglitazone (ROG) has an inhibitory effect on HMGB1 (high mobility group box 1), a pro-inflammatory DNA-binding nuclear protein, inducing the epithelial cells to become mesenchymal-like cells and supporting the pathogenesis of eosinophilic chronic rhinosinusitis with nasal polyps ECRSwNP [ 49 ]. The agonist ROG reverted the effect of rhHMGB1 on EMT in ECRSwNP cells as well as the endogenous expression of HMGB1 induced by the treatment with lipopolysaccharide (LPS).…”

Section: Intra-cellular Signaling Transduction Mechanisms Underlyimentioning

confidence: 99%

“…The agonist ROG reverted the effect of rhHMGB1 on EMT in ECRSwNP cells as well as the endogenous expression of HMGB1 induced by the treatment with lipopolysaccharide (LPS). ROG is able to restore the effects of HMGB1 activation up-regulating the expression of Zonula occludens-1 (ZO-1) and E-cadherin, and down-regulating the expression of N-cadherin and vimentin, biomarkers of MSCs [ 49 ].…”

Section: Intra-cellular Signaling Transduction Mechanisms Underlyimentioning

confidence: 99%

Nasal Polyposis: Insights in Epithelial-Mesenchymal Transition and Differentiation of Polyp Mesenchymal Stem Cells

Chiarella

Lombardo

Lobello

et al. 2020

IJMS

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Chronic rhinosinusitis is a common inflammatory disease of paranasal sinuses, which causes rhinorrhea, nasal congestion, and hyposmia. The genetic predisposition or the exposure to irritants can sustain the inflammatory response and the development of nasal polyposis. Nasal polyps are benign and teardrop-shaped growths that project in the nasal cavities, and originate from the ethmoid sinuses. This inflammatory process is associated with high expression of IL-4, IL-5 and IL-13 and IgE. Antibodies targeting these cytokines or receptors represent a therapeutic strategy in the treatment of nasal polyposis in combination with corticosteroids. The molecular pathogenesis of nasal polyps in chronic rhinosinusitis (CRS) patients is associated with remodeling transition, a process in which epithelial cells lose their typical phenotype, acquiring a mesenchymal-like aspect. TGFβ/SMAD, ERK, and Wnt/β-catenin pathways are altered during the nasal tissue remodeling. miRNA and inhibitor molecules targeting these signaling pathways are able to interfere with the process; which could lead to alternative therapies. Nasal polyps are an alternative source of mesenchymal stem cells, which can be isolated from surgical biopsies. A molecular understanding of the biology of PO-MSCs will contribute to the delineating inflammatory process underlying the development of nasal polyps.

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“…PPARγ signaling pathway is also involved in EMT in CRSwNP. It has been shown that Rosiglitazone (ROG), a PPAR-γ agonist, has a inhibitory effect on HMGB1 (High Mobility Group Box 1), a pro-inflammatory DNA-binding nuclear protein, inducing the epithelial cells to become mesenchymal-like cells and supporting the pathogenesis of eosinophilic chronic rhinosinusitis with nasal polyps ECRSwNP [42]. ROG reverted the effect of rhHMGB1 on EMT in ECRSwNP cells as well as the endogenous expression of HMGB1 induced by the treatment with the lipopolysaccharide (LPS).…”

Section: Pparγ Signaling Pathway Is Involved In Crswnpmentioning

confidence: 99%

“…ROG reverted the effect of rhHMGB1 on EMT in ECRSwNP cells as well as the endogenous expression of HMGB1 induced by the treatment with the lipopolysaccharide (LPS). ROG is able to restore the effects of HMGB1 activation up-regulating the expression of ZO-1 (Zonula occludens-1) and E-cadherin and down-regulating the expression of N-cadherin and vimentin [42].…”

Section: Pparγ Signaling Pathway Is Involved In Crswnpmentioning

confidence: 99%

Nasal Polyposis: Insights in Epithelial-mesenchymal Transition and Differentiation of Polyp Mesenchymal Stem Cells

Chiarella

Lombardo

Lobello

et al. 2020

Preprint

View full text Add to dashboard Cite

Chronic rhinosinusitis is a common inflammatory disease of paranasal sinuses, which causes rhinorrhea, nasal congestion and hyposmia. The genetic predisposition or the exposure to irritants can sustain the inflammatory response and the development of nasal polyposis. Nasal polyps are benign and teardrop-shaped growths that project in the nasal cavities and originate from the ethmoid sinuses. This inflammatory process is associated with high expression of IL-5 cytokine and infiltration of eosinophils. Humanized monoclonal antibodies targeting IL-5 or its receptor, represent a therapeutic strategy in the treatment of nasal polyposis in combination with corticosteroids. The molecular pathogenesis of nasal polyps in CRS patients is associated to the epithelial-mesenchymal transition (EMT), a process in which epithelial cells lose their typical phenotype acquiring a mesenchymal phenotype. TGFβ/SMAD, ERK, and Wnt/β-catenin pathways are altered in EMT during the nasal tissue remodeling. miRNA and inhibitor molecules targeting these altered signaling pathways are able to interfere with EMT; which could lead to alternative therapies. Nasal polyps are an alternative source of mesenchymal stem cells which can be easily isolated from surgical biopsies. A molecular understanding of the biology of PO-MSCs will contribute to delineating inflammatory process underlying the development of nasal polyps.

show abstract

Agonist of PPAR-γ Reduced Epithelial-Mesenchymal Transition in Eosinophilic Chronic Rhinosinusitis with Nasal Polyps via Inhibition of High Mobility Group Box1

Cited by 23 publications

References 63 publications

Snail upregulates FN and LEF transcription negatively feed backed by PPAR-gamma: a general model established for Snail to transactivate mesenchymal genes

Snail upregulates FN and LEF transcription negatively feed backed by PPAR-gamma: a general model established for Snail to transactivate mesenchymal genes

Nasal Polyposis: Insights in Epithelial-Mesenchymal Transition and Differentiation of Polyp Mesenchymal Stem Cells

Nasal Polyposis: Insights in Epithelial-mesenchymal Transition and Differentiation of Polyp Mesenchymal Stem Cells

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