Impaired microRNA processing enhances cellular transformation and tumorigenesis (original) (raw)

Nature Genetics volume 39, pages 673–677 (2007)Cite this article

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 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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Acknowledgements

We thank R. Shiekhattar for the Flag-Dicer1 cDNA construct; V.N. Kim for the Flag-DGCR8 and Flag-Drosha cDNA constructs and P.A. Sharp for the pRL-TK and pGL3 constructs. We thank A. Ventura, P. Sandy, M. Winslow, H. Zhang and members of the Sharp laboratory for experimental advice and assistance. We also thank R. Bronson and M.E. McLaughlin for histological analysis. We acknowledge C. Bender Kim, M. Winslow, C. Reinhardt and S. Kissler for critical review of the manuscript. This work was supported by grant 2-PO1-CA42063-21 from the National Cancer Institute and by Cancer Center Support grant P30-CA14051 from the National Cancer Institute. M.S.K. is an NSF Graduate Research Fellow. T.J. is a Ludwig Scholar. T.R.G. and T.J. are investigators of the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. MIT Center for Cancer Research, Cambridge, 02139, Massachusetts, USA
    Madhu S Kumar, Kim L Mercer & Tyler Jacks
  2. Broad Institute of MIT and Harvard, Cambridge, 02141, Massachusetts, USA
    Jun Lu & Todd R Golub
  3. Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, 02115, Massachusetts, USA
    Jun Lu & Todd R Golub
  4. Howard Hughes Medical Institute, Harvard Medical School, Boston, 02115, Massachusetts, USA
    Todd R Golub
  5. Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA
    Tyler Jacks

Authors

  1. Madhu S Kumar
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  2. Jun Lu
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  3. Kim L Mercer
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  4. Todd R Golub
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  5. Tyler Jacks
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Contributions

M.S.K. and J.L. conceived the project. M.S.K., J.L. and K.L.M. carried out all experiments described. T.R.G. and T.J. supervised the experimental work and interpretation of data. The manuscript was prepared by M.S.K. and T.J.

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Correspondence toTyler Jacks.

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The authors declare no competing financial interests.

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Kumar, M., Lu, J., Mercer, K. et al. Impaired microRNA processing enhances cellular transformation and tumorigenesis.Nat Genet 39, 673–677 (2007). https://doi.org/10.1038/ng2003

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