Abstract
ABSTRACTBackground: Epithelial-to-mesenchymal transition (EMT) is a key step in the transformation of epithelial cells into migratory and invasive tumour cells. Intricate positive and negative regulatory processes regulate EMT. Many oncogenic signalling pathways can induce EMT, but the specific mechanisms of how this occurs, and how this process is controlled are not fully understood.Methods: RNA-Seq analysis, computational analysis of protein networks and large-scale cancer genomics datasets were used to identify ELF3 as a negative regulator of the expression of EMT markers. Western blotting coupled to siRNA as well as analysis of tumour/normal colorectal cancer panels was used to investigate the expression and function of ELF3.Results: RNA-Seq analysis of colorectal cancer cells expressing mutant and wild-type β-catenin and analysis of colorectal cancer cells expressing inducible mutant RAS showed that ELF3 expression is reduced in response to oncogenic signalling and antagonizes Wnt and RAS oncogenic signalling pathways. Analysis of gene-expression patterns across The Cancer Genome Atlas (TCGA) and protein localization in colorectal cancer tumour panels showed that ELF3 expression is anti-correlated with β-catenin and markers of EMT and correlates with better clinical prognosis.Conclusions: ELF3 is a negative regulator of the EMT transcription factor (EMT-TF) ZEB1 through its function as an antagonist of oncogenic signalling.
Highlights
Epithelial-to-mesenchymal (EMT) transition is a central step in the acquisition of a migratory and invasive phenotype by cancer cells in epithelial tumours, through loss of cell-cell adhesion and cell polarity 1
Despite the depth of study of E-cadherin and its function during Epithelial-to-mesenchymal transition (EMT), relatively little is known about how the epithelial state is maintained and of factors that repress EMT in cancer cells by antagonizing oncogenic signalling, transcription factors such as OVOL1, OVOL2 9,10 and GRLH2 11,12 that maintain the epithelial state or induce mesenchymal-to-epithelial transition (MET) in human cancers have been described
Using RNA-Seq analysis of colorectal cancer cells expressing wild-type or oncogenic βcatenin, we identified genes regulated by oncogenic Wnt signalling in colorectal cancer cells
Summary
Epithelial-to-mesenchymal (EMT) transition is a central step in the acquisition of a migratory and invasive phenotype by cancer cells in epithelial tumours, through loss of cell-cell adhesion and cell polarity 1. EMT inducers can enhance oncogenic signaling through multiple molecular mechanisms; Snail can promote expression of Wnt target genes through interaction with β-catenin 6, and loss of ZEB1 mediated repression of E-cadherin enables nuclear localization of oncogenic β-catenin 7. Despite the depth of study of E-cadherin and its function during EMT, relatively little is known about how the epithelial state is maintained and of factors that repress EMT in cancer cells by antagonizing oncogenic signalling, transcription factors such as OVOL1, OVOL2 9,10 and GRLH2 11,12 that maintain the epithelial state or induce mesenchymal-to-epithelial transition (MET) in human cancers have been described. Many oncogenic signalling pathways can induce EMT, but the specific mechanisms of how this occurs, and how this process is controlled are not fully understood
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