Abstract 3538: Obligate haploinsufficiency of the microRNA-processing molecule dicer1 in a murine colitis-associated tumorigenesis model

Abstract

Abstract Background: A widespread downregulated expression of microRNAs (miRNAs) is commonly observed in human cancers. Similarly, deregulated expression of miRNA-processing pathway components, which results in the reduction of global miRNA expression, may also be associated with tumorigenesis. Thus, we hypothesized that the deregulation of microRNA-processing molecule Dicer1 in intestinal epithelial cells may accelerate intestinal inflammation-associated tumorigenesis. Methods & Results: We constructed Dicer1 gene-disrupted mice with monoallelic and biallelic loss of its locus. Inflammation-associated colon tumors were induced by azoxymethane (AOM) injection with the treatment by three cycles of Dextran Sulfate Sodium (DSS). 1) Dicer1 protein expression and subsequent mature miRNA levels in the isolated intestinal epithelial cells were inversely correlated with the number of intact Dicer1 alleles. 2) Although the severity of inflammation after the induction 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. 3) 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. 4) While the expression levels of representative oncogenes and tumor suppressor genes were in most cases inversely correlated with the expression levels of Dicer1, some genes were not affected by Dicer1 deletion. Conclusion: Specific ablation of Dicer1 in intestinal epithelial cells accelerates intestinal inflammation-associated tumorigenesis. However, this effect was apparent only when a single copy of Dicer1 was deleted, but not with complete Dicer1 gene ablation. Generally, complete loss of the function of most tumor suppressor genes is advantageous for tumor development. However, our results suggest that, in case of Dicer1 gene, complete loss is deleterious for cancer development, while its partial inactivation promotes tumor formation. This unique “obligate haploinsufficient role” colitis-associated colon tumor of Dicer and miRNAs needs further attention to elucidate the pathogenesis of tumorigenesis related with deregulated miRNAs. Citation Format: Takeshi Yoshikawa, Motoyuki Otsuka, Kazuhiko Koike. Obligate haploinsufficiency of the microRNA-processing molecule dicer1 in a murine colitis-associated tumorigenesis model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3538. doi:10.1158/1538-7445.AM2014-3538