title: Overexpression of microRNAs-155 and 21 targeting mismatch repair proteins in inflammatory bowel diseases.
abstract: Microsatellite instability (MSI) due to mismatch repair (MMR) deficiency is reported in 5-10% of colorectal cancers (CRCs) complicating inflammatory bowel diseases (IBD). The molecular mechanisms underlying MMR deficiency may be different in IBD CRCs, and in sporadic and hereditary MSI tumors. Here, we hypothesize that overexpression of miR-155 and miR-21, two inflammation-related microRNAs 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 microsatellite stable (n = 10) IBD CRCs, and in MSI (n = 32) and microsatellite stable (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 overexpressed not only in the colonic mucosa of IBD subjects without CRC but also in neoplastic tissues of IBD patients compared with non-IBD controls (P < 0.001). Importantly, in patients with IBD CRCs, miR-155 and miR-21 overexpression extended to the distant non-neoplastic mucosa (P < 0.001). Ratios of expressions in tumors versus matched distant mucosa revealed a nearly significant association between miR-155 overexpression and MSI in IBDs (P = 0.057). These results show a strong deregulation of both MMR-targeting microRNAs in IBD subjects with or without cancer. MiR-155 overexpression 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.
authors.affiliation: INSERM/UMR S 938 - Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancers, Equipe Labellisée Ligue Contre le Cancer, Paris, France. magali.svrcek@sat.aphp.fr
authors.forename: Magali
authors.initials: M
authors.lastname: Svrcek
authors.forename: Nizar
authors.initials: N
authors.lastname: El-Murr
authors.forename: Kristell
authors.initials: K
authors.lastname: Wanherdrick
authors.forename: Sylvie
authors.initials: S
authors.lastname: Dumont
authors.forename: Laurent
authors.initials: L
authors.lastname: Beaugerie
authors.forename: Jacques
authors.initials: J
authors.lastname: Cosnes
authors.forename: Jean-Frédéric
authors.initials: JF
authors.lastname: Colombel
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Tiret
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Fléjou
authors.forename: Thécla
authors.initials: T
authors.lastname: Lesuffleur
authors.forename: Alex
authors.initials: A
authors.lastname: Duval
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000235:genetics*; D053843:DNA Mismatch Repair; D005260:Female; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics*; D007413:Intestinal Mucosa / Q000166:cytology; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D053842:Microsatellite Instability; D008875:Middle Aged; D055815:Young Adult
chemical_list: C524942:MIRN155 microRNA, human; C524940:MIRN21 microRNA, human; D035683:MicroRNAs