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

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.

MicroRNA Biogenesis and Hedgehog-Patched Signaling Cooperate to Regulate an Important Developmental Transition in Granule Cell Development

“…Further to this, monoallelic Dicer1 loss exerted an effect, which indicates that Dicer1 is also a haploinsufficient tumor suppressor gene. These findings are consistent with the role of Dicer1 in other tumor types (Arrate et al 2010;Lambertz et al 2010;Nittner et al 2012;Yoshikawa et al 2013;Zhang et al 2014).…”

Dicer1 Phosphomimetic Promotes Tumor Progression and Dissemination

“…DICER1 is an essential ribo-endonuclease that processes pre-miRNAs into functional miRNAs (1)(2)(3). DICER1 acts as a haploinsufficient tumor suppressor: somatic heterozygous mutations are frequently observed in human cancers and heterozygosity promotes tumorigenesis in several murine tumor models (4)(5)(6)(7)(8).…”

Constitutive Dicer1 phosphorylation accelerates metabolism and aging in vivo

“…For example, patients with DICER1 syndrome with heterozygous germline mutations in DICER1 (missense and truncating) present with multinodular goiter, macrocephaly, global developmental delay, lung cysts, overgrowth, and increased risk for a variety of cancers (3,4). Similarly, conditional mouse models with loss of Dicer1 in a tissue-specific manner point to Dicer1's role in regulating insulin resistance, one aspect of aging (17,41,44), spermatogenesis (35,36), oocyte meiotic maturation (38), melanogenesis (10), and a variety of cancers (5)(6)(7)(8). Our studies show that constitutive phosphorylation of Dicer1 also causes disease.…”

“…These patients present with multinodular goiter, macrocephaly, global developmental delay, lung cysts, overgrowth, and increased risk for a variety of cancers (3,4). DICER1 somatic heterozygous mutations are also frequently observed in human cancers (5)(6)(7)(8). These data highlight the relevance of DICER1 in human disease.…”