Impaired microRNA processing enhances cellular transformation and tumorigenesis.

Nat Genet
Authors
Keywords
Abstract

MicroRNAs (miRNAs) are a new class of small noncoding RNAs that post-transcriptionally regulate the expression of target mRNA transcripts. Many of these target mRNA transcripts are involved in proliferation, differentiation and apoptosis, processes commonly altered during tumorigenesis. Recent work has shown a global decrease of mature miRNA expression in human cancers. However, it is unclear whether this global repression of miRNAs reflects the undifferentiated state of tumors or causally contributes to the transformed phenotype. Here we show that global repression of miRNA maturation promotes cellular transformation and tumorigenesis. Cancer cells expressing short hairpin RNAs (shRNAs) targeting three different components of the miRNA processing machinery showed a substantial decrease in steady-state miRNA levels and a more pronounced transformed phenotype. In animals, miRNA processing-impaired cells formed tumors with accelerated kinetics. These tumors were more invasive than control tumors, suggesting that global miRNA loss enhances tumorigenesis. Furthermore, conditional deletion of Dicer1 enhanced tumor development in a K-Ras-induced mouse model of lung cancer. Overall, these studies indicate that abrogation of global miRNA processing promotes tumorigenesis.

Year of Publication
2007
Journal
Nat Genet
Volume
39
Issue
5
Pages
673-7
Date Published
2007 May
ISSN
1061-4036
URL
DOI
10.1038/ng2003
PubMed ID
17401365
Links
Grant list
2-P01-CA42063-21 / CA / NCI NIH HHS / United States
P30-CA14051 / CA / NCI NIH HHS / United States