Abstract
Epithelial–mesenchymal transition (EMT) is a drastic phenotypic change during cancer metastasis and is one of the most important hallmarks of aggressive cancer. Although the overexpression of some specific transcription factors explains the functional alteration of EMT-induced cells, a complete picture of this biological process is yet to be elucidated. To comprehensively profile EMT-related genes in colorectal cancer, we quantified the EMT induction ability of each gene according to its similarity to the cancer stromal gene signature and termed it “mesenchymal score.” This bioinformatic approach successfully identified 90 candidate EMT mediators, which are strongly predictive of survival in clinical samples. Among these candidates, we discovered that the neuronal gene ARC, possibly originating from the retrotransposon, unexpectedly plays a crucial role in EMT induction. Profiling of novel EMT mediators we demonstrated here may help understand the complexity of the EMT program and open up new avenues for therapeutic intervention in colorectal cancer.
Highlights
Epithelial–mesenchymal transition (EMT) is a drastic phenotypic change during cancer metastasis and is one of the most important hallmarks of aggressive cancer
Mesenchymal scores were significantly higher for eight known mesenchymal markers (VIM, SNAI2, ZEB1, ZEB2, Twist Family BHLH Transcription Factor 1 (TWIST1), Cadherin 2 (CDH2), Transforming Growth Factor Beta 1 (TGFB1), and Forkhead Box C2 (FOXC2)) than eight randomly selected genes (p < 0.001) (Fig. 1b)
Genes preferably expressed in stromal tissue tended to have high mesenchymal scores, we found a subset of genes dominantly expressed in the cancer epithelium despite their high mesenchymal scores. We focused on this subpopulation because genes preferably expressed in the cancer epithelium with high mesenchymal scores could be upstream molecules in the EMT pathway and may have an active function
Summary
Epithelial–mesenchymal transition (EMT) is a drastic phenotypic change during cancer metastasis and is one of the most important hallmarks of aggressive cancer. To comprehensively profile EMT-related genes in colorectal cancer, we quantified the EMT induction ability of each gene according to its similarity to the cancer stromal gene signature and termed it “mesenchymal score.” This bioinformatic approach successfully identified 90 candidate EMT mediators, which are strongly predictive of survival in clinical samples. In 2015, two reports elegantly demonstrated that stromal tissue is the primary origin of the EMT signature in CRC bulk samples and that what we considered to be gene expression profiles of EMT-induced cancer cells might be that of contaminated stromal components[24,25]. ARC has been studied in neuroscience, the association between ARC and human malignancy has been reported in detail for the first time
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