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Title: Exploring the role of sphingolipid machinery during the epithelial to mesenchymal transition program using an integrative approach
Authors: Meshcheryakova, A
Svoboda, M
Tahir, A
Köfeler, H.C
Triebl, A 
Mungenast, F
Heinze, G
Gerner, C
Zimmermann, P
Jaritz, M
Mechtcheriakova, D
Keywords: ABC transporter A1
breast cancer resistance protein
lysophosphatidic acid
lysophosphatidic acid receptor
messenger RNA
multidrug resistance associated protein 1
sphingosine 1 phosphate
sphingosine 1 phosphate receptor
transforming growth factor beta
tumor marker
tumor necrosis factor alpha
unclassified enzyme
bladder cancer
cancer model
cancer tissue
colorectal cancer
controlled study
down regulation
epithelial mesenchymal transition
gene control
gene expression profiling
gene expression regulation
genetic association
genetic transcription
human cell
Influenza virus
lipid analysis
lung adenocarcinoma
lung cancer
lung cancer cell line
lung carcinogenesis
mass spectrometry
multigene family
prostate cancer
signal transduction
sphingolipid metabolism
tissue microarray
virus carcinogenesis
epithelial mesenchymal transition
gene regulatory network
lipid metabolism
tumor cell line
Cell Line, Tumor
Epithelial-Mesenchymal Transition
Gene Regulatory Networks
Lipid Metabolism
Issue Date: 2016
Citation: Meshcheryakova, A, Svoboda, M, Tahir, A, Köfeler, H.C, Triebl, A, Mungenast, F, Heinze, G, Gerner, C, Zimmermann, P, Jaritz, M, Mechtcheriakova, D (2016). Exploring the role of sphingolipid machinery during the epithelial to mesenchymal transition program using an integrative approach. Oncotarget 7 (16) : 22295-22323. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
Abstract: The epithelial to mesenchymal transition (EMT) program is activated in epithelial cancer cells and facilitates their ability to metastasize based on enhanced migratory, proliferative, anti-apoptotic, and pluripotent capacities. Given the fundamental impact of sphingolipid machinery to each individual process, the sphingolipid-related mechanisms might be considered among the most prominent drivers/players of EMT; yet, there is still limited knowledge. Given the complexity of the interconnected sphingolipid system, which includes distinct sphingolipid mediators, their synthesizing enzymes, receptors and transporters, we herein apply an integrative approach for assessment of the sphingolipid-associated mechanisms underlying EMT program. We created the sphingolipid-/EMT-relevant 41-gene/23-gene signatures which were applied to denote transcriptional events in a lung cancer cell-based EMT model. Based on defined 35-gene sphingolipid/EMT-attributed signature of regulated genes, we show close associations between EMT markers, genes comprising the sphingolipid network at multiple levels and encoding sphingosine 1-phosphate (S1P)-/ceramide-metabolizing enzymes, S1P and lysophosphatidic acid (LPA) receptors and S1P transporters, pluripotency genes and inflammation-related molecules, and demonstrate the underlying biological pathways and regulators. Mass spectrometry-based sphingolipid analysis revealed an EMT-attributed shift towards increased S1P and LPA accompanied by reduced ceramide levels. Notably, using transcriptomics data across various cell-based perturbations and neoplastic tissues (24193 arrays), we identified the sphingolipid/EMT signature primarily in lung adenocarcinoma tissues; besides, bladder, colorectal and prostate cancers were among the top-ranked. The findings also highlight novel regulatory associations between influenza virus and the sphingolipid/EMT-associated mechanisms. In sum, data propose the multidimensional contribution of sphingolipid machinery to pathological EMT and may yield new biomarkers and therapeutic targets.
Source Title: Oncotarget
ISSN: 19492553
DOI: 10.18632/oncotarget.7947
Rights: Attribution 4.0 International
Appears in Collections:Staff Publications

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