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| Status |
Public on Dec 27, 2019 |
| Title |
Chronic IL-1β-induced inflammation regulates epithelial-to-mesenchymal transition memory phenotypes via epigenetic modifications in non-small cell lung cancer |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Chronic inflammation facilitates tumor progression. We discovered that a subset of non-small cell lung cancer cells underwent a gradually progressing epithelial-to-mesenchymal (EMT) phenotype following a 21-day exposure to IL-1β, an abundant proinflammatory cytokine in the at-risk for lung cancer pulmonary and the lung tumor microenvironments. Pathway analysis of the gene expression profile and in vitro functional studies revealed that the EMT and EMT-associated phenotypes, including enhanced cell invasion, PD-L1 upregulation, and chemoresistance, were sustained in the absence of continuous IL-1β exposure. We referred to this phenomenon as EMT memory. Utilizing a doxycycline-controlled SLUG expression system, we found that high expression of the transcription factor SLUG was indispensable for the establishment of EMT memory. High SLUG expression in tumors of lung cancer patients was associated with poor survival. Chemical or genetic inhibition of SLUG upregulation prevented EMT following the acute IL-1β exposure but did not reverse EMT memory. Chromatin immunoprecipitation and methylation-specific PCR further revealed a SLUG-mediated temporal regulation of epigenetic modifications, including accumulation of H3K27, H3K9, and DNA methylation, in the CDH1 (E-cadherin) promoter following the chronic IL-1β exposure. Chemical inhibition of DNA methylation not only restored E-cadherin expression in EMT memory, but also primed cells for chemotherapy-induced apoptosis.
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| Overall design |
Compare transcriptome profiles between IL-1β treated and control untreated A549 cells at different time points. Each biological condition was represented by triplicate.
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| Contributor(s) |
Li R, Ong SL, Tran LM, Jing Z, Huang ZL, Liu B, Lee G, Salehi-Rad R, Krysan K, Pagano PC, Paul MK, Xu S, Herschman HR, Dubinett SM, Park SJ, Walser TC, Heinrich EL, Crosson WP |
| Citation(s) |
31941995 |
| Submission date |
Dec 26, 2019 |
| Last update date |
Mar 27, 2020 |
| Contact name |
Linh My Tran |
| E-mail(s) |
linhtran@ucla.edu
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| Organization name |
University of Los Angeles
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| Department |
Medicine - Pulmonary & Critical Care
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| Lab |
Dubinett Lab
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| Street address |
Box 951690, 37-131 CHS
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| City |
Los Angeles |
| State/province |
California |
| ZIP/Postal code |
90095-1690 |
| Country |
USA |
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| Platforms (1) |
| GPL21290 |
Illumina HiSeq 3000 (Homo sapiens) |
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| Samples (36)
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| Relations |
| BioProject |
PRJNA597764 |
| SRA |
SRP238840 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE142620_RAW.tar |
7.5 Mb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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