High expression of epithelial-mesenchymal transition (EMT) markers in malignant mesothelioma and possible therapeutic intervention using an N-cadherin antagonist

Suraokar, Milind; Lin, HungYun; He, Dongxu; Llansa, Norma; Mendoza, Gabriela; Woods, Denise M.; Prudkin, Ludmila; Lee, J. J.; Wistuba, I.; Tsao, A.S.

doi:10.1200/jco.2008.26.15_suppl.8067

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“…The analysis of cell lines confirmed that they were characterized by cells of higher invasion ability (JU77 and MSTO-H211) in contrast with the low invasive NCI-H28. Our observations were consistent with previous studies in which a high level of N-cadherin and a low level of E-cadherin in MSTO-H211 cells were observed [55,56]. Additionally, we revealed that EPE treatment resulted in the downregulation of Snail and ZEB-1-two crucial transcription factors engaged in EMT regulation-as well as N-cadherin and vimentin, the main mesenchymal markers [57,58].…”

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confidence: 93%

Evening Primrose Extract Modulates TYMS Expression via SP1 Transcription Factor in Malignant Pleural Mesothelioma

Chmielewska-Kassassir,

Sobierajska,

Ciszewski

et al. 2023

Cancers

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Purpose: To determine the mechanism of EPE in downregulating TYMS in MPM cancer. Methods: The TYMS mRNA expression with epithelial-to-mesenchymal transition biomarkers and nuclear factor SP1 was assessed using the GEO database in a data set of MPM patients (GSE51024). Invasive MPM cell lines were in vitro models for the investigation of TYMS expression after EPE treatment. The tyms promoter SP1 binding sequences were determined using Genomatix v 3.4 software Electrophoretic mobility shift and dual-luciferase reporter assays revealed specific SP1 motifs in the interaction of EPE and reference compounds. Chromatin immunoprecipitation and Re-ChIP were used for the co-occupancy study. Results: In MPM patients, a positive correlation of overexpressed TYMS with mesenchymal TWIST1, FN1 and N-cadherin was observed. EPE and its major components, gallic and ellagic acid (GA and EA, respectively), downregulated TYMS in invasive MPM cells by interacting with particular SP1 motifs on the tyms promoter. The luciferase constructs confirmed the occupation of two SP1 regulatory regions critical for the promotion of TYMS expression. Both EPE and reference standards influenced SP1 translocation into the nucleus. Conclusion: EPE components reduced TYMS expression by occupation of SP1 motifs on the tyms promoter and reversed the EMT phenotype of invasive MPM cells. Further in-depth analysis of the molecular docking of polyphenol compounds with SP1 regulatory motifs is required.

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