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The aggressiveness of colorectal cancer in kidney transplantation is much more significant than the increase in its incidence compared with the general population. The molecular mechanism of the different immnosuppressive drugs with antagonistic antineoplasic properties is not well characterized. Exosomes (Ex) are involved in tumor immunity, angiogenesis and metastasis. Exosomal miRNAs can affect expression of a variety of target genes. Our aim is to investigate if distinct colon cancer cells treated with Cyclosporin A (CsA) and Rapamycin (RAPA) can induce the production of different Ex content that could explain the cancer progression in kidney transplantation.Metastatic (HCT116) and non metastatic (SW480) cells were treated with CsA and RAPA. Ex isolation was made by differential ultracentrifugation and Ex characterization by nanoparticle tracking analysis, flow cytometry, and electron microscopy. A comparative miRNAs profile by Affymetrix miRNA 4.1 Array Strips was made in miRNAs isolated from Ex released from conditioned cells under CsA and RAPA.Bioinformatics analysis indicated that miR6787-5p, miR6746-5p, miR6127 were common and highly differentially expressed in Ex from HCT116 after both drugs. These miRNAs were down-regulated by CsA and up-regulated by RAPA in Ex from HCT116. These data were not shown in SW480 derived Ex. We identified putative target genes related to the miRNAs implicated in the NOTCH signaling, and in immunoregulatory/inflammatory processes.In conclusion, CsA and RAPA induce a different exosomal miRNAs expression pattern in metastatic cancer cell line, not evidenced in non-metastatic cells. Exosomal miRNAs could be a potential biomarker in cancer progression and metastasis.