Epithelial-to-mesenchymal transition (EMT) in cancer cells, represents early stages of metastasisand 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.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 . To escape from the primary tumour site and to form metastatic lesions, epithelial cancer cells must acquire a more migratory phenotype to overcome several anatomical barriers. The process of conversion of the epithelial cell phenotype towards a more mesenchymal phenotype (EMT process) is considered to be an initial and critical for metastasis. Although there are many concepts of how EMT is modified in cancer, (reviewed by Gurzu et al. 2 ), the mechanism of EMT is still incompletely elucidated and there are many conflicting results published. During cancer EMT, there is a dynamic modulation of the interplay between transcription factors, gene expression and miRNAs (microRNAs /small non-coding RNAs) 3 . Thus, the understanding of the molecular interactions during the phenotype switch towards more mesenchymal and invasive cells has become important for future therapeutic strategies.We previously performed a global transcriptomic and phenotypic characteristic of the HT29 colorectal adenocarcinoma cell line affected by the transcription factor Snail (Snai1), a core regulator of the early stages of the epithelial phenotype conversion that initiates metastasis. We have shown that upregulation of Snail in HT29 cells results in an incomplete phenotype conversion, up to the intermediate epithelial state 4 . We and others have found that enhanced Snail expression is associated with a more aggressive phenotype, poorer clinical outc...
Neuromedin U (NMU), a neuropeptide isolated from porcine spinal cord and named because of its activity as a rat uterus smooth muscle contraction inducer, is emerging as a new player in the tumorigenesis and/or metastasis of many types of cancers. Expressed in a variety of tissues, NMU has been shown to possess many important activities in the central nervous system as well as on the periphery. Along with the main structural and functional features of NMU and its currently known receptors, we summarized a growing number of recently published data from different tissues and cells that associate NMU activity with cancer development and progression. We ask if, based on current reports, NMU can be included as a marker of these processes and/or considered as a therapeutic target.
Colorectal cancer (CRC) presents significant molecular heterogeneity. The cellular plasticity of epithelial to mesenchymal transition (EMT) is one of the key factors responsible for the heterogeneous nature of metastatic CRC. EMT is an important regulator of ATP binding cassette (ABC) protein expression; these proteins are the active transporters of a broad range of endogenous compounds and anticancer drugs. In our previous studies, we performed a transcriptomic and functional analysis of CRC in the early stages of metastasis induced by the overexpression of Snail, the transcription factor involved in EMT initiation. Interestingly, we found a correlation between the Snail expression and ABCC4 (MRP4) protein upregulation. The relationship between epithelial transition and ABCC4 expression and function in CRC has not been previously defined. In the current study, we propose that the ABCC4 expression changes during EMT and may be differentially regulated in various subpopulations of CRC. We confirmed that ABCC4 upregulation is correlated with the phenotype conversion process in CRC. The analysis of Gene Expression Omnibus (GEO) sets showed that the ABCC4 expression was elevated in CRC patients. The results of a functional study demonstrated that, in CRC, ABCC4 can regulate cell migration in a cyclic nucleotide-dependent manner.
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