Abstract
BackgroundmiR-182-5p (miR-182) is an oncogenic microRNA (miRNA) found in different tumor types and one of the most up-regulated miRNA in colorectal cancer (CRC). Although this microRNA is expressed in the early steps of tumor development, its role in driving tumorigenesis is unclear.MethodsThe effects of miR-182 silencing on transcriptomic profile were investigated using two CRC cell lines characterized by different in vivo biological behavior, the MICOL-14h-tert cell line (dormant upon transfer into immunodeficient hosts) and its tumorigenic variant, MICOL-14tum. Apoptosis was studied by annexin/PI staining and cleaved Caspase-3/PARP analysis. The effect of miR-182 silencing on the tumorigenic potential was addressed in a xenogeneic model of MICOL-14tum transplant.ResultsEndogenous miR-182 expression was higher in MICOL-14tum than in MICOL-14h-tert cells. Interestingly, miR-182 silencing had a strong impact on gene expression profile, and the positive regulation of apoptotic process was one of the most affected pathways. Accordingly, annexin/PI staining and caspase-3/PARP activation demonstrated that miR-182 treatment significantly increased apoptosis, with a prominent effect in MICOL-14tum cells. Moreover, a significant modulation of the cell cycle profile was exerted by anti-miR-182 treatment only in MICOL-14tum cells, where a significant increase in the fraction of cells in G0/G1 phases was observed. Accordingly, a significant growth reduction and a less aggressive histological aspect were observed in tumor masses generated by in vivo transfer of anti-miR-182-treated MICOL-14tum cells into immunodeficient hosts.ConclusionsAltogether, these data indicate that increased miR-182 expression may promote cell proliferation, suppress the apoptotic pathway and ultimately confer aggressive traits on CRC cells.
Highlights
MiR-182-5p is an oncogenic microRNA found in different tumor types and one of the most up-regulated miRNA in colorectal cancer (CRC)
The CG-705 cell line was derived from a primary tumor of the right colon; MICOL-S cell line was derived from the hepatic metastasis of a primary right colon cancer; the MICOL-14h-tert cell line was derived from a lymph-node metastasis of a patient with rectal cancer
Results miR-182 is up-regulated in CRC cell lines and can be efficiently silenced in tumorigenic and non-tumorigenic cell lines miR-182 expression levels were evaluated by qRT-PCR in normal colon mucosa samples as a reference, and in a panel of seven CRC cell lines
Summary
MiR-182-5p (miR-182) is an oncogenic microRNA (miRNA) found in different tumor types and one of the most up-regulated miRNA in colorectal cancer (CRC). This microRNA is expressed in the early steps of tumor development, its role in driving tumorigenesis is unclear. MicroRNAs (miRNAs) regulate fundamental cellular processes, such as proliferation, differentiation, migration, angiogenesis and apoptosis, by repressing translation or inducing cleavage of their targets. In reference to CRC development, we identified miR182-5p (miR-182) as one of the most up-regulated miRNAs in primary tumors compared to normal colon mucosa, suggesting its potential impact on target genes de-regulated in CRC [19]. Plasma miR-182 concentrations were higher in CRC patients at stage IV than in controls, and significantly decreased 1 month after radical hepatic metastasectomy, indicating that evaluation of circulating miR-182 may integrate the array of non-invasive blood-based monitoring and screening biomarkers [20]
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