Dataset Information

Exploring the role of sphingolipid machinery during the epithelial to mesenchymal transition program using an integrative approach.

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.

SUBMITTER: Meshcheryakova A

PROVIDER: S-EPMC5008362 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Exploring the role of sphingolipid machinery during the epithelial to mesenchymal transition program using an integrative approach.

Meshcheryakova Anastasia A Svoboda Martin M Tahir Ammar A Köfeler Harald C HC Triebl Alexander A Mungenast Felicitas F Heinze Georg G Gerner Christopher C Zimmermann Philip P Jaritz Markus M Mechtcheriakova Diana D

Oncotarget 20160401 16

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 sp ...[more]

PMID: 26967245

Similar Datasets

Project description:The airway epithelium is a semi-impermeable barrier whose disruption by growth factor reprogramming is associated with chronic airway diseases of humans. Transforming growth factor beta (TGF?)-induced epithelial mesenchymal transition (EMT) plays important roles in airway remodeling characteristic of idiopathic lung fibrosis, asthma and chronic obstructive pulmonary disease (COPD). Inflammation of the airways leads to airway injury and tumor necrosis factor alpha (TNF?) plays an important pro-inflammatory role. Little systematic information about the effects of EMT on TNF? signaling is available. Using an in vitro model of TGF?-induced EMT in primary human small airway epithelial cells (hSAECs), we applied quantitative proteomics and phosphoprotein profiling to understand the molecular mechanism of EMT and the impact of EMT on innate inflammatory responses. We quantified 7925 proteins and 1348 phosphorylation sites by stable isotope labeling with iTRAQ technology. We found that cellular response to TNF? is cell state dependent and the relative TNF? response in mesenchymal state is highly compressed. Combined bioinformatics analyses of proteome and phosphoproteome indicate that the EMT state is associated with reprogramming of kinome, signaling cascade of upstream transcription regulators, phosphor-networks, and NF-?B dependent cell signaling.Epithelial mesenchymal transition and inflammation have important implications for clinical and physiologic manifestations of chronic airway diseases such as severe asthma, COPD, and lung fibrosis. Little systematic information on the interplay between EMT and innate inflammation is available. This study combined quantitative proteomics and phosphorproteomics approach to obtain systems-level insight into the upstream transcription regulators involved in the TGF?-induced EMT in primary human small airway epithelial cells and to elucidate how EMT impacts on the TNF? signaling pathways. The proteomics and phosphoproteomics analysis indicates that many signaling pathways involved in TGF?-induced EMT and EMT has profound reprogramming effects on innate inflammation response.

Project description:Epithelial-to-mesenchymal transition (EMT) is a key biological process involved in a multitude of developmental and pathological events. It is characterized by the progressive loss of cell-to-cell contacts and actin cytoskeletal rearrangements, leading to filopodia formation and the progressive up-regulation of a mesenchymal gene expression pattern enabling cell migration. Epithelial-to-mesenchymal transition is already observed in early embryonic stages such as gastrulation, when the epiblast undergoes an EMT process and therefore leads to the formation of the third embryonic layer, the mesoderm. Epithelial-to-mesenchymal transition is pivotal in multiple embryonic processes, such as for example during cardiovascular system development, as valve primordia are formed and the cardiac jelly is progressively invaded by endocardium-derived mesenchyme or as the external cardiac cell layer is established, i.e., the epicardium and cells detached migrate into the embryonic myocardial to form the cardiac fibrous skeleton and the coronary vasculature. Strikingly, the most important biological event in which EMT is pivotal is cancer development and metastasis. Over the last years, understanding of the transcriptional regulatory networks involved in EMT has greatly advanced. Several transcriptional factors such as Snail, Slug, Twist, Zeb1 and Zeb2 have been reported to play fundamental roles in EMT, leading in most cases to transcriptional repression of cell?cell interacting proteins such as ZO-1 and cadherins and activation of cytoskeletal markers such as vimentin. In recent years, a fundamental role for non-coding RNAs, particularly microRNAs and more recently long non-coding RNAs, has been identified in normal tissue development and homeostasis as well as in several oncogenic processes. In this study, we will provide a state-of-the-art review of the functional roles of non-coding RNAs, particularly microRNAs, in epithelial-to-mesenchymal transition in both developmental and pathological EMT.

Dataset Information

Exploring the role of sphingolipid machinery during the epithelial to mesenchymal transition program using an integrative approach.

Publications

Exploring the role of sphingolipid machinery during the epithelial to mesenchymal transition program using an integrative approach.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets