Unique Haploinsufficient Role of the MicroRNA-Processing Molecule Dicer1 in a Murine Colitis-Associated Tumorigenesis Model

Takeshi Yoshikawa,Motoyuki Otsuka,Akemi Takata,Haruhiko Yoshida,Motoko Ohno,Takahiro Kishikawa,Chikako Shibata,Young Jun Kang,Kazuhiko Koike,Yue Wang

doi:10.1371/journal.pone.0071969

Takeshi Yoshikawa, Motoyuki Otsuka + Show 8 more

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https://doi.org/10.1371/journal.pone.0071969

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Abstract

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. Here, we show that specific ablation of Dicer1 in intestinal epithelial cells accelerates intestinal inflammation-associated tumorigenesis. This effect was apparent only when a single copy of Dicer1 was deleted, but not with complete Dicer1 ablation. DICER expression and subsequent mature miRNA levels were inversely correlated with the number of intact Dicer1 alleles. Because the expression levels of DICER were retained in tumors and its surrounding tissues even after induction of colitis-associated tumors, the effects of Dicer1 deletion were cell-autonomous. Although the expression levels of representative oncogenes and tumor suppressor genes were in most cases inversely correlated with the expression levels of DICER, some genes were not affected by Dicer1 deletion. Thus, deregulating the delicate balance between the expression levels of tumor-promoting and -suppressive genes may be crucial for tumorigenesis in this unique haploinsufficient case.

Highlights

While microRNAs can function as both tumor suppressors and oncogenes in tumor development [1,2,3], widespread downregulated expression of miRNAs promotes cellular transformation and tumorigenesis and is commonly observed in human cancers [1,4,5]
Intestinal epithelial cell-specific Dicer1-mutant mice To determine the function of Dicer and its downstream miRNAs in intestinal epithelia, we generated mutant mice lacking Dicer in intestinal epithelial cells (VillinCre-DicerD/D) by crossing loxP-flanked (Dicerfl/fl) mice with villin promoter drivenCre (VillinCre)-expressing mice
The functional levels of DICER, determined by the abundance of representative mature miRNAs in the colon epithelia of control and mutant mice, appeared to proportionally reflect the deletion of Dicer1 alleles (Figure 1c and d). These results suggest that Dicer was successfully ablated in the intestinal epithelial cells of VillinCre-DicerD/D homozygous and VillinCre-DicerD/+ heterozygous mice, and suggest that the expression levels of DICER and subsequent function of miRNA maturation were proportionally dependent on the number of mutant alleles

Summary

Introduction

While microRNAs (miRNAs) can function as both tumor suppressors and oncogenes in tumor development [1,2,3], widespread downregulated expression of miRNAs promotes cellular transformation and tumorigenesis and is commonly observed in human cancers [1,4,5]. A defect in Dicer is one possible mechanism of global downregulated expression of mature miRNAs. Mutations in Dicer were identified in pediatric tumor pleuropulmonary blastoma, Sertoli-Leydig cell tumors, or other tumors [13,14] and downregulation of DICER is associated with poor prognosis of ovarian cancers and other tumors [11,15,16]. Mutations in Dicer were identified in pediatric tumor pleuropulmonary blastoma, Sertoli-Leydig cell tumors, or other tumors [13,14] and downregulation of DICER is associated with poor prognosis of ovarian cancers and other tumors [11,15,16] These clinical observations, together with experimental results showing the global loss of mature miRNAs induced by Dicer knockdown in vitro and in vivo, demonstrates that Dicer is functionally relevant to oncogenesis [17]

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