Exploring the role of sphingolipid machinery during the epithelial to mesenchymal transition program using an integrative approach
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Anastasia Meshcheryakova1, Martin Svoboda1,*, Ammar Tahir2,3,*, Harald C. Köfeler4, Alexander Triebl4, Felicitas Mungenast1, Georg Heinze5, Christopher Gerner2,3, Philip Zimmermann6, Markus Jaritz7, Diana Mechtcheriakova1
1Department of Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria
2Institute of Analytical Chemistry, University of Vienna, Vienna, Austria
3Mass Spectrometry Center, University of Vienna, Vienna, Austria
4Core Facility for Mass Spectrometry, Center for Medical Research, Medical University of Graz, Graz, Austria
5Section for Clinical Biometrics, Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University Vienna, Vienna, Austria
6Nebion AG, Zürich, Switzerland
7Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria
*These authors have contributed equally to this work
Diana Mechtcheriakova, e-mail: firstname.lastname@example.org
Keywords: sphingolipid-related targets, sphingosine 1-phosphate/ceramide rheostat, multigene signature, epithelial to mesenchymal transition, lung cancer
Received: July 13, 2015 Accepted: February 20, 2016 Published: March 07, 2016
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.
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