Dicer1 functions as a haploinsufficient tumor suppressor.

Genes Dev
Authors
Keywords
Abstract

While the global down-regulation of microRNAs (miRNAs) is a common feature of human tumors, its genetic basis is largely undefined. To explore this question, we analyzed the consequences of conditional Dicer1 mutation (Dicer1 "floxed" or Dicer1(fl)) on several mouse models of cancer. Here we show Dicer1 functions as a haploinsufficient tumor suppressor gene. Deletion of a single copy of Dicer1 in tumors from Dicer1(fl/+) animals led to reduced survival compared with controls. These tumors exhibited impaired miRNA processing but failed to lose the wild-type Dicer1 allele. Moreover, tumors from Dicer1(fl/fl) animals always maintained one functional Dicer1 allele. Consistent with selection against full loss of Dicer1 expression, enforced Dicer1 deletion caused inhibition of tumorigenesis. Analysis of human cancer genome copy number data reveals frequent deletion of DICER1. Importantly, however, the gene has not been reported to undergo homozygous deletion, suggesting that DICER1 is haploinsufficient in human cancer. These findings suggest Dicer1 may be an important haploinsufficient tumor suppressor gene and, furthermore, that other factors controlling miRNA biogenesis may also function in this manner.

Year of Publication
2009
Journal
Genes Dev
Volume
23
Issue
23
Pages
2700-4
Date Published
2009 Dec 01
ISSN
1549-5477
URL
DOI
10.1101/gad.1848209
PubMed ID
19903759
PubMed Central ID
PMC2788328
Links
Grant list
P01 CA042063 / CA / NCI NIH HHS / United States
P30 CA014051 / CA / NCI NIH HHS / United States
2-PO1-CA42063 / CA / NCI NIH HHS / United States
P30-CA14051 / CA / NCI NIH HHS / United States