Over Expression of MicroRNAs-155 and 21 Targeting Mismatch Repair Proteins in Inflammatory Bowel Diseases
Menée sur des échantillons de tissus tumoraux et de tissus sains prélevés sur plusieurs cohortes de patients, cette étude suggère que la surexpression du micro-ARN 155, impliqué dans la régulation des protéines de réparation des mésappariements de l'ADN, est associée au développement précoce d'un cancer colorectal chez les patients atteints d'une maladie inflammatoire intestinale
Microsatellite instability (MSI) due to mismatch repair (MMR) deficiency is reported in 5-10% of colorectal cancers complicating inflammatory bowel diseases (IBD-CRCs). The molecular mechanisms underlying MMR-deficiency may be different in IBD-CRCs, and in sporadic and hereditary MSI tumours. Here we hypothesize that over-expression of miR-155 and miR-21, two inflammation-related miRNAs that target core MMR proteins, may constitute a pre-neoplastic event for the development of MSI IBD-CRCs. We studied miR-155 and miR-21 expression using Real-Time Quantitative PCR in MSI (n=10) and MSS (microsatellite stable, n=10) IBD-CRCs, and in MSI (n=32) and MSS (n=30) non-IBD CRCs. We also screened colonic samples from IBD patients without cancer (n=18) and used healthy colonic mucosa as controls (n=20). MiR-155 and miR-21 appeared significantly over-expressed in the colonic mucosa of IBD subjects without CRC, but also in neoplastic tissues of IBD patients compared to non-IBD controls (p<0.001). Importantly, in patients with IBD-CRCs, miR-155 and miR-21 over-expression extended to the distant non-neoplastic mucosa (p<0.001). Ratios of expressions in tumours versus matched distant mucosa revealed a nearly significant association between miR-155 over-expression and MSI in IBDs (p=0.057). These results show a strong deregulation of both MMR-targeting miRNAs in IBD subjects with or without cancer. MiR-155 over-expression being particularly associated to MSI IBD-CRCs and extending to distant non-neoplastic mucosa, strongly suggests that a pre-neoplastic miR-155 field defect may promote MSI-driven transformation of the colonic mucosa. The detection and monitoring of miR-155 field defect may therefore have implications for the prevention and treatment of MSI IBD-CRCs.
Carcinogenesis , résumé, 2013