Endoplasmic reticulum stress as a novel target to ameliorate epithelial-to-mesenchymal transition and apoptosis of human peritoneal mesothelial cells

Shin, Hyun Soo; Ryu, Eun Sun; Oh, Eok Soo; Kang, Duk Hee

doi:10.1038/labinvest.2015.91

Cited by 37 publications

(31 citation statements)

References 57 publications

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“…EMT is one of the earliest mechanisms of peritoneal fibrosis 4, 5, 22 . Mesothelial cells are known to undergo EMT to become matrix-producing myofibroblasts under pathologic conditions and participate in the pathogenesis of peritoneal fibrosis 4, 5, 7, 23–25 . Therefore, pharmacological prevention and/or reversal of EMT may serve as one of the possible therapeutic approaches to peritoneal fibrosis.…”

Section: Discussionmentioning

confidence: 99%

“…Human peritoneal mesothelial cells (HPMCs) were isolated from human omentum and maintained using a modified method of previous publication 7 . Tissue collection was approved by the ethics committee of Ewha Womans University Mok-Dong Hospital and informed consent was obtained from each patient.…”

Section: Methodsmentioning

confidence: 99%

“…Accumulating evidences suggest epithelial-to-mesenchymal transition (EMT) as an early mechanism for peritoneal fibrosis 3–5 . Myofibroblasts produced in the process of EMT are known to provide an unfavorable environment for the preservation of peritoneal membrane via generation of pro-fibrotic cytokines and reactive oxygen species (ROS) 6, 7 . Despite recent controversies on EMT as a source of myofibroblast in the kidney and liver 8, 9 , previous data implicates EMT as a potential therapeutic target for preventing peritoneal fibrosis 3–5 .…”

Section: Introductionmentioning

confidence: 99%

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Metformin ameliorates the Phenotype Transition of Peritoneal Mesothelial Cells and Peritoneal Fibrosis via a modulation of Oxidative Stress

Shin

Kim

et al. 2017

Sci Rep

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Phenotype transition of peritoneum is an early mechanism of peritoneal fibrosis. Metformin, 5′-adenosine monophosphate-activated protein kinase (AMPK) activator, has recently received a new attention due to its preventive effect on organ fibrosis and cancer metastasis by inhibiting epithelial-to-mesenchymal transition (EMT). We investigated the effect of metformin on EMT of human peritoneal mesothelial cells (HPMC) and animal model of peritoneal dialysis (PD). TGF-β1-induced EMT in HPMC was ameliorated by metformin. Metformin alleviated NAPDH oxidase- and mitochondria-mediated ROS production with an increase in superoxide dismutase (SOD) activity and SOD2 expression. Metformin inhibited the activation of Smad2/3 and MAPK, GSK-3β phosphorylation, nuclear translocalization of β-catenin and Snail in HPMCs. Effect of metformin on TGF-β1-induced EMT was ameliorated by either AMPK inhibitor or AMPK gene silencing. Another AMPK agonist, 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide partially blocked TGF-β1-induced EMT. In animal model of PD, intraperitoneal metformin decreased the peritoneal thickness and EMT with an increase in ratio of reduced to oxidized glutathione and the expression of SOD whereas it decreased the expression of nitrotyrosine and 8-hydroxy-2′-deoxyguanosine. Therefore, a modulation of AMPK in peritoneum can be a novel tool to prevent peritoneal fibrosis by providing a favorable oxidant/anti-oxidant milieu in peritoneal cavity and ameliorating phenotype transition of peritoneal mesothelial cells.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Metformin ameliorates the Phenotype Transition of Peritoneal Mesothelial Cells and Peritoneal Fibrosis via a modulation of Oxidative Stress

Shin

Kim

et al. 2017

Sci Rep

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“…Human peritoneal mesothelial cells (HPMCs) were isolated using the method of Shin et al (23). In brief, a piece of human omentum, obtained from consenting patients undergoing elective abdominal surgery, was washed in HBSS and incubated in 0.05% Trypsin-0.02% EDTA solution for 20 min at 37°C with continuous agitation.…”

Section: Cell Culturementioning

confidence: 99%

Paricalcitol attenuates TGF‐β1–induced phenotype transition of human peritoneal mesothelial cells (HPMCs)viamodulation of oxidative stress and NLRP3 inflammasome

Kang

Kim

et al. 2018

FASEB j.

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Phenotype transition of mesothelial cells, such as epithelial‐to‐mesenchymal transition (EMT), is one of the early mechanisms of peritoneal fibrosis, which is mediated by oxidative stress and inflammation. Nucleotide‐binding oligomerization domain‐like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a multiprotein oligomer that promotes the maturation of IL‐lβ and IL‐18. Paricalcitol is reported to exert an antiinflammatory effect; however, there are no studies as to whether paricalcitol modulates the activation of NLRP3 inflammasome. We investigated the role of NLRP3 inflammasome in peritoneal EMT with an exploration of the effect of paricalcitol on oxidative stress, NLRP3 inflammasome, and EMT of mesothelial cells. TGF‐βl‐induced EMT in human peritoneal mesothelial cells (HPMCs) was associated with an up‐regulation of NLRP3, apoptosis‐associated speck‐like protein containing a caspase recruitment domain (ASC), and ρrocasρase‐1, with an increased production of IL‐lβ and IL‐18, which was ameliorated by small interfering (si)NLRP3, siASC, caspase inhibitors, or neutralizing antibodies for IL‐lβ and IL‐18. TGF‐βl enhanced reactive oxygen species generation with an increase in NADPH oxidase (NOX) activity and mitochondrial NOX4 production. Paricalcitol alleviated TGF‐βl‐induced EMT and the NLRP3 inflammasome, which was associated with a down‐regulation of NOX activity by interfering with p47phox and p22phox interaction and mitochondrial NOX4 production in HPMCs. Taken together, paricalcitol ameliorated EMT of HPMCs via modulating an NOX‐dependent increase in the activity of NLRP3 inflammasome. Paricalcitol could be a novel approach to protect the peritoneum from the development of EMT and peritoneal fibrosis.—Ko, J., Kang, H.‐J., Kim, D.‐A., Ryu, E.‐S., Yu, M., Lee, H., Lee, H. K., Ryu, H.‐M., Park, S.‐H., Kim, Y.‐L., Kang, D.‐H. Paricalcitol attenuates TGF‐βl–induced phenotype transition of human peritoneal mesothelial cells (HPMCs) via modulation of oxidative stress and NLRP3 inflammasome. FASEB J. 33, 3035–3050 (2019). http://www.fasebj.org

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“…S3). Subsequent GO analysis revealed that these genes were also significantly 7 associated with EMT-related biological processes including response to endoplasmic reticulum stress [13] , response to wounding, cell-substrate adhesion, integrin-mediated signaling pathway [14] , and extracellular structure organization. Besides, IKBIP seemed to be more associated with neutrophil mediated immunity, suggesting that IKBIP upregulation was accompanied by immunosuppression of GBM, which indicated a more malignant characteristic in glioma.…”

Section: A and B)mentioning

confidence: 99%

IKBIP is a novel EMT-related biomarker and predicts poor survival in glioma

Yang¹,

Wang

et al. 2020

Preprint

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Purpose I kappa B-interacting protein (IKBIP) in cancer has rarely been reported.This study aimed at investigating its expression pattern and biological function in brain glioma at transcriptional level. MethodsWe selected 301 glioma patients with microarray data from CGGA database and 697 glioma patients with RNAseq data from TCGA database. Transcriptome data and clinical data of 998 samples were analyzed. Statistical analysis and figure generating were performed with R language. ResultsWe found that IKBIP expression showed positive correlation with WHO grade of glioma. IKBIP was increased in IDH wildtype and mesenchymal molecular subtype of glioma. Gene ontology analysis demonstrated that IKBIP was profoundly associated with extracellular matrix organization, cell-substrate adhesion and response to wounding in both pan-glioma and glioblastoma. Subsequent GSEA analysis revealed that IKBIP was particularly correlated with epithelial-to-mesenchymal transition (EMT). To further elucidate the relationship between IKBIP and EMT, we performed GSVA analysis to screen the EMT-related signaling pathways, and found that IKBIP expression was significantly associated with PI3K/AKT, hypoxia and TGF-β pathway. Moreover, IKBIP expression was found to be synergistic with key biomarkers of EMT, especially with N-cadherin, vimentin, snail, slug and TWIST1.Finally, higher IKBIP indicated significantly shorter survival for glioma patients.Conclusions IKBIP was associated with more aggressive phenotypes of gliomas. 3 Furthermore, IKBIP was significantly involved in EMT and could serve as an independent prognosticator in glioma.

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Endoplasmic reticulum stress as a novel target to ameliorate epithelial-to-mesenchymal transition and apoptosis of human peritoneal mesothelial cells

Cited by 37 publications

References 57 publications

Metformin ameliorates the Phenotype Transition of Peritoneal Mesothelial Cells and Peritoneal Fibrosis via a modulation of Oxidative Stress

Metformin ameliorates the Phenotype Transition of Peritoneal Mesothelial Cells and Peritoneal Fibrosis via a modulation of Oxidative Stress

Paricalcitol attenuates TGF‐β1–induced phenotype transition of human peritoneal mesothelial cells (HPMCs)viamodulation of oxidative stress and NLRP3 inflammasome

IKBIP is a novel EMT-related biomarker and predicts poor survival in glioma

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