Abstract
Epithelial-to-mesenchymal transition (EMT) in cancer cells, represents early stages of metastasis and is a promising target in colorectal cancer (CRC) therapy. There have been many attempts to identify markers and key pathways induced throughout EMT but the process is complex and depends on the cancer type and tumour microenvironment. Here we used the colon cancer cell line HT29, which stably overexpressed Snail, the key transcription factor in early EMT, as a model for colorectal adenocarcinoma cells with a pro-metastatic phenotype. We investigated miRNA expression regulation during that phenotypic switching. We found that overexpression of Snail in HT29 cells triggered significant changes in individual miRNA levels but did not change the global efficiency of miRNA processing. Snail abundance repressed the expression of miR-192 and miR-194 and increased miR-205, let-7i and SNORD13 levels. These identified changes correlated with the reported transcriptomic alterations in Snail-overexpressing HT29 cells. We also investigated how Snail affected the miRNA content of extracellular vesicles (EVs) released from HT29 cells. Our data suggest that the presence of Snail significantly alters the complex mRNA/miRNA interactions in the early steps of metastasis and also has an impact on the content of EVs released from HT29 cells.
Highlights
According to the newest projections published by the American Cancer Society, despite significant overall reductions in colorectal cancer (CRC) incidence and mortality, there is a need for further efforts to advance therapies on the early stage of cancer and metastasis development[1]
We demonstrated that downregulation of metastasis suppressors, miR-192 and miR-194, can be associated with Snail binding to the pri-miR-192/194 precursor promoter
We showed that Snail induces the upregulation of miR-205 and let-7i, which is reflected in the content of extracellular vesicles released from Snail-overexpressing HT29 cells
Summary
According to the newest projections published by the American Cancer Society, despite significant overall reductions in colorectal cancer (CRC) incidence and mortality, there is a need for further efforts to advance therapies on the early stage of cancer and metastasis development[1]. We posit that Snail-overexpressing HT29 cells represent the phenotype of cancer cells at the leading edge of the primary tumour, with a more invasive phenotype, that are prepared for escape from the primary niche. Since their discovery, vast amounts of miRNAs have been described and a growing number of correlations between miRNA expression and the development of cancer and cancer metastasis has been reported[7,8]. Defined group of miRNAs has been shown to provide high diagnostic accuracy, for instance in breast cancers[12], knowledge of the molecular mechanisms and regulatory networks leading to miRNA regulation over the course of EMT induction in CRC is still limited[13]. We showed that Snail induces the upregulation of miR-205 and let-7i, which is reflected in the content of extracellular vesicles released from Snail-overexpressing HT29 cells
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