Enhancing microRNA function may prevent colon carcinogenesis

Background: Because a widespread down-regulated expression of microRNAs (miRNAs) is commonly observed in human cancers, we hypothesized that the de-regulation of microRNA-processing molecule Dicer in intestinal epithelial cells may accelerate colon tumorigenesis. In addition, we screened drug libraries to identify compounds clinically applicable to prevent colon tumorigenesis caused by such pathogenesis. Methods & Results: We constructed Dicer1 gene-disrupted mice. Colon tumors were induced by a standard AOM-DSS model. Dicer1 protein expression and subsequent mature miRNA levels in the isolated intestinal epithelial cells were inversely correlated with the number of intact Dicer1 alleles. Although the severity of inflammation in this model was comparable in control and Dicer1-mutant mice, the number of colon tumors was significantly higher in heterozygous mice but not in homozygous mice. Because the expression levels of Dicer1 were retained in tumors and its surrounding tissues even after induction of colitis-associated tumors, the effects of Dicer1 deletion on tumorigenesis were considered as cell-autonomous. From screening over 1,500 kinds of chemical compounds, we identified a compound which may be applicable for the prevention of intestinal tumorigenesis by its augmentation of miRNA function. Conclusion: Our results suggest that complete loss of Dicer and miRNAs is deleterious for cancer development, while its partial inactivation promotes tumor formation. This unique obligate haploinsufficient role of Dicer and miRNAs in colon tumorigenesis may be prevented by our identified drug which augments miRNA function.