Abstract
BackgroundChronic inflammation associated with ulcerative colitis predisposes individuals to increased colon cancer risk. The aim of these studies was to identify microRNAs that are aberrantly regulated during inflammation and may participate in transformation of colonic epithelial cells in the inflammatory setting.Methodology/Principal FindingsWe have use quantitative PCR arrays to compare microRNA (miRNA) expression in tumors and control colonic epithelial cells isolated from distal colons of chronically inflamed mice and APCMin/+ mice. Rank order statistics was utilized to identify differentially regulated miRNAs in tumors that arose due to chronic inflammation and/or to germline APC mutation. Eight high priority miRNAs were identified: miR-215, miR-137, miR-708, miR-31, and miR-135b were differentially expressed in APC tumors and miR-215, miR-133a, miR-467d, miR-218, miR-708, miR-31, and miR-135b in colitis-associated tumors. Four of these (miR-215, miR-708, miR-31, and miR-135b) were common to both tumors types, and dysregulation of these miRNAs was confirmed in an independent sample set. Target prediction and pathway analysis suggests that these microRNAs, in the aggregate, regulate signaling pathways related to MAPK, PI3K, WNT, and TGF-β, all of which are known to be involved in transformation.Conclusions/SignificanceWe conclude that these four miRNAs are dysregulated at some very early stage in transformation of colonic epithelial cells. This response is not dependent on the mechanism of initiation of transformation (inflammation versus germline mutation), suggesting that the miRNAs that we have identified are likely to regulate critical signaling pathways that are central to early events in transformation of colonic epithelial cells.
Highlights
MicroRNAs are a class of small noncoding RNAs of 19 to 22 nucleotides implicated in a number of important cellular processes such as development, differentiation, proliferation, cell cycle progression, apoptosis, inflammation, and stress responses [1,2,3,4,5,6,7,8]
Quantification of miRNA expression in tissue samples is complicated by the fact that one has no obvious direct means to identify appropriate endogenous controls that may be used to normalize expression data and correct for differences in the amount of RNA analyzed or the efficiency of miRNA extraction or cDNA conversion in samples from different tissues. This potential problem is acute in the studies such as those that will be described below in which we undertake to compare miRNA abundance in tissues derived from mice of different ages, diets, inflammatory status, and tumor burden
Our central objective was to compare miRNA expression in colon tumors that arise due to chronic inflammation and germ line mutations in model systems
Summary
MicroRNAs (miRNAs) are a class of small noncoding RNAs of 19 to 22 nucleotides implicated in a number of important cellular processes such as development, differentiation, proliferation, cell cycle progression, apoptosis, inflammation, and stress responses [1,2,3,4,5,6,7,8]. Little is known about the functional consequence of dysregulation of miRNAs during chronic colitis in epithelial cells, and even less on tumorigenesis. Limited, these studies do provide the precident that deregulation of a subset of microRNAs during chronic colitis may be associated with neoplastic and metaplastic metaplastic transformation. These studies do provide the precident that deregulation of a subset of microRNAs during chronic colitis may be associated with neoplastic and metaplastic metaplastic transformation To this end, microRNAs may be useful biomarkers to help predict risk for malignancy in patients with long standing active disease. These miRNAs have the potential to control both anti-oncogenic and pro-oncogenic transcriptional networks, thereby influencing tumorigenic outcome
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
