Letter abstract


Nature Genetics 39, 673 - 677 (2007)
Published online: 1 April 2007 | doi:10.1038/ng2003

Impaired microRNA processing enhances cellular transformation and tumorigenesis

Madhu S Kumar1, Jun Lu2,3, Kim L Mercer1, Todd R Golub2,3,4 & Tyler Jacks1,5

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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 apoptosis1, 2, processes commonly altered during tumorigenesis. Recent work has shown a global decrease of mature miRNA expression in human cancers3. 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.

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  1. MIT Center for Cancer Research, Cambridge, Massachusetts 02139, USA.
  2. Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02141, USA.
  3. Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA.
  4. Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
  5. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

Correspondence to: Tyler Jacks1,5 e-mail: tjacks@mit.edu

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