Abstract
BackgroundColorectal cancer (CRC) is a life-threatening complication of ulcerative colitis (UC), and patients are routinely screened for the development of precancerous lesions (dysplasia). However, rates of CRC development in patients with confirmed low-grade dysplasia vary widely between studies, suggesting a large degree of heterogeneity between these lesions that is not detectable macroscopically. A better understanding of the underlying molecular changes that occur in dysplasia will help to identify lesions at higher risk of malignancy. MicroRNAs (miRNAs) post-transcriptionally regulate protein expression and cell-signalling networks. Aberrant miRNA expression is a feature of sporadic CRC but much less is known about the changes that occur in dysplasia and in UC.MethodsComprehensive microRNA profiling was performed on RNA extracted from UC dysplastic lesions (n = 7) and UC controls (n = 10). The expression of miRNAs in UC post inflammatory polyps (n = 7) was also assessed. Candidate miRNAs were further validated by qPCR, and miRNA in situ hybridization. Serum levels of miRNAs were also assessed with a view to identification of non-invasive biomarkers of dysplasia.ResultsUC dysplasia was associated with a shift in miRNA expression profiles that was not seen in inflammatory polyps. In particular, levels of miR-200b-3p were increased in dysplasia, and this miRNA was localised to epithelial cells in dysplastic lesions and in UC cancers. No changes in miRNA levels were detected in the serum.ConclusionUC-Dysplasia is linked to altered miRNA expression in the mucosa and elevated miR-200b-3p levels.
Highlights
Inflammatory bowel diseases (IBD), which include ulcerative colitis (UC), are characterised by uncontrolled intestinal inflammation
UC dysplasia was associated with a shift in miRNA expression profiles that was not seen in inflammatory polyps
Levels of miR-200b-3p were increased in dysplasia, and this miRNA was localised to epithelial cells in dysplastic lesions and in UC cancers
Summary
Inflammatory bowel diseases (IBD), which include ulcerative colitis (UC), are characterised by uncontrolled intestinal inflammation. Colorectal cancer (CRC) is a life-threatening complication of UC, and UC patients are estimated to be at a 2.4 fold increased risk of CRC relative to the general population.[1] The risk of CRC in UC patients increases considerably with duration and extent of active inflammation, diagnosis at a younger age, concomitant primary sclerosing cholangitis (PSC) and family history of CRC.[2,3] Relative to sporadic CRC, UC associated CRC (UC-CRC) is linked to an earlier age of onset and higher rates of mortality; in one study, 59% of UC-CRC patients had died at 5-years of follow-up.[3]. Given the increased risk of UC-CRC, it is necessary to screen UC patients for the development of precancerous lesions (dysplasia), with periodic chromoendoscopies starting 8–10 years after the first appearance of colitis-associated symptoms.[4,5] During surveillance procedures, targeted biopsies are collected from suspect lesions and assessed by pathologists. Colorectal cancer (CRC) is a life-threatening complication of ulcerative colitis (UC), and patients are routinely screened for the development of precancerous lesions (dysplasia).
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