High Glucose Restraint of Acetylcholine-Induced Keratinocyte Epithelial-Mesenchymal Transition Is Mitigated by p38 Inhibition

Tan, Mark Wei Yi; Tan, Wei; Kong, Ze Qing; Toh, Jun Hong; Wee, Jonathan Wei Kiat; Teo, Erica Mei Ling; Cheng, Hong Sheng; Wang, Xiaomeng; Tan, Nguan Soon

doi:10.1016/j.jid.2020.10.026

Cited by 10 publications

(4 citation statements)

References 37 publications

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“…Recent in vivo studies have indicated hyperglycemia had a strong influence on the therapeutic outcome of applied therapeutics (Gnyawali et al 2020 ; Tan et al 2021 ). Thus, prior to evaluating the therapeutic actions of CoPP, a reliable and physiologically relevant in vitro model was established (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Clinical studies have revealed that several therapeutic agents that promote diabetic wound healing, could also increase the chances of diabetic patients developing cancers (Sundaram et al 2018 ). It was found that in addition to inducing apoptosis in keratinocytes, hyperglycemia was found to restrain cutaneous epithelial plasticity, which was necessary for functional wound closure (Tan et al 2021 ). This may explain why excessive therapeutic agents are often needed to achieve successful wound closure in diabetic wounds.…”

Section: Discussionmentioning

confidence: 99%

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Cobalt protoporphyrin promotes human keratinocyte migration under hyperglycemic conditions

Fang

Lai²,

Chen³

et al. 2022

Mol Med

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Background Complete healing of diabetic wounds continues to be a clinically unmet need. Although robust therapies such as stem cell therapy and growth factor treatment are clinically applied, these treatments are costly for most diabetic wound patients. Therefore, a cheaper alternative is needed. Cobalt protoporphyrin (CoPP) has recently been demonstrated to promote tissue regeneration. In this study, the therapeutic benefits of CoPP in diabetic wound healing were examined. Methods An in vitro wound healing model that mimics re-epithelialization was established to examine the effect of CoPP on the migratory capability of human keratinocytes (HaCaT) in either normal glucose (NG) or high glucose (HG) media, as well as in the presence of either H2O2 or lipopolysaccharide (LPS). At the end of the migration assays, cells were collected and subjected to Western blotting analysis and immunostaining. Results HaCaT were found to migrate significantly more slowly in the HG media compared to the NG media. CoPP treatment was found to enhance cell migration in HG media, but was found to decrease cell migration and proliferation when HaCaT were cultured in NG media. CoPP treatment induced high levels of expression of Nrf-2/HO-1 and FoxO1 in HaCaT cultured in either glucose concentration, although the FoxO1 expression was found to be significantly higher in HaCaT that underwent the migration assay in NG media compared to those in HG media. The higher level of FoxO1 expression seen in CoPP-treated HaCaT cultured in NG media resulted in upregulation of CCL20 and downregulation of TGFβ1. In contrast, HaCaT migrated in HG media were found to have high levels of expression of TGFβ1, and low levels of expression of CCL20. Interestingly, in the presence of H2O2, CoPP-pretreated HaCaT cultured in either NG or HG media had similar expression level of Nrf-2/HO-1 and FoxO1 to each other. Moreover, the anti-apoptotic effect of CoPP pretreatment was noticed in HaCaT cultured in either glucose concentration. Additionally, CoPP pretreatment was shown to promote tight junction formation in HaCaT suffering from LPS-induced damage. Conclusions CoPP enhances cell migratory capacity under hyperglycemic conditions, and protects cells from oxidative and LPS-induced cellular damage in HG media containing either H2O2 or LPS.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cobalt protoporphyrin promotes human keratinocyte migration under hyperglycemic conditions

Fang

Lai²,

Chen³

et al. 2022

Mol Med

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“…The polarized human gastric adenocarcinoma cell line MKN74 and the human epidermal keratinocyte cell line HaCaT were cultured as previously described. [ 7 , 26 ] YTN3, YTN5, and YTN16, N‐methyl‐N‐nitrosourea ‐induced murine glandular stomach carcinoma cells, were kind gifts from Prof. Tetsuya Tsukamoto (Fujita Health University, Aichi, Japan). [ 19 ] Human breast carcinoma, MCF7 and hepatocellular carcinoma, HepG2, were purchased from American Type Culture Collection and cultured in RPMI‐1640 and DMEM supplemented with 10% FBS, respectively.…”

Section: Methodsmentioning

confidence: 99%

YWHAG Deficiency Disrupts the EMT‐Associated Network to Induce Oxidative Cell Death and Prevent Metastasis

Lee,

Tan,

Low

et al. 2023

Advanced Science

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Metastasis involves epithelial‐to‐mesenchymal transition (EMT), a process that is regulated by complex gene networks, where their deliberate disruption may yield a promising outcome. However, little is known about mechanisms that coordinate these metastasis‐associated networks. To address this gap, hub genes with broad engagement across various human cancers by analyzing the transcriptomes of different cancer cell types undergoing EMT are identified. The oncogenic signaling adaptor protein tyrosine 3‐monooxygenase/tryptophan 5‐monooxygenase activation protein gamma (YWHAG) is ranked top for its clinical relevance and impact. The cellular kinome and transcriptome data are surveyed to construct the regulome of YWHAG, revealing stress responses and metabolic processes during cancer EMT. It is demonstrated that a YWHAG‐dependent cytoprotective mechanism in the regulome is embedded in EMT‐associated networks to protect cancer cells from oxidative catastrophe through enhanced autophagy during EMT. YWHAG deficiency results in a rapid accumulation of reactive oxygen species (ROS), delayed EMT, and cell death. Tumor allografts show that metastasis potential and overall survival time are correlated with the YWHAG expression level of cancer cell lines. Metastasized tumors have higher expression of YWHAG and autophagy‐related genes than primary tumors. Silencing YWHAG diminishes primary tumor volumes, prevents metastasis, and prolongs the median survival period of the mice.

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“…Total RNA was reverse transcribed using iScript cDNA SuperMix (Quanta Biosciences, USA). Quantitative PCR was performed as previously described [185]. Immunoblots were performed as previously described [186].…”

Section: Real-time Pcr and Immunoblotsmentioning

confidence: 99%

Mechanoregulation of angiopoietin-like 4 in epithelial-mesenchymal transition and cancer metastasis

Liao

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The contributions of the co-authors are as follows:• I performed the RNA-seq and microarray data mining, quality control of RNA-seq data, processing of raw RNA-seq data into unified FeatureCounts files for bioinformatics analysis, analysis of RNA-seq data, generation of new RNA-seq data (3D cultured MKN74 cells), characterization of cancer cell spheroids, characterization of 3D collagen-alginate and PEGDA-GelMA cultures, cell imaging, most of the qPCR works, most of the dose response studies, identification of DNAse I hypersensitive regions in human Angptl4 gene, qChIP and animal studies.• H.S. Cheng wrote the codes for RNA-seq data analysis and provided mentorship to me whenever necessary.• J.J.H. Lim performed the experiments on bladder cancer cells and mined the cancer clinical data from databases as part of his undergraduate final year project.• J.X.T. Lee generated the RNA-seq data for 2D cultured MKN74 cells.• M.I.G. Vos and Y.S. Yip provided support to me for animal studies and imaging.• J.J.H. Lim and D. Chua performed the immunoblots.• D. Chua also performed the re-ChIP and zymography.• C.B. Too performed the ASO knockdown and assisted in the imaging of MKN74 spheroids.

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High Glucose Restraint of Acetylcholine-Induced Keratinocyte Epithelial-Mesenchymal Transition Is Mitigated by p38 Inhibition

Cited by 10 publications

References 37 publications

Cobalt protoporphyrin promotes human keratinocyte migration under hyperglycemic conditions

Cobalt protoporphyrin promotes human keratinocyte migration under hyperglycemic conditions

YWHAG Deficiency Disrupts the EMT‐Associated Network to Induce Oxidative Cell Death and Prevent Metastasis

Mechanoregulation of angiopoietin-like 4 in epithelial-mesenchymal transition and cancer metastasis

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