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Impaired microRNA processing enhances cellular transformation and tumorigenesis

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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Figure 1: Impaired miRNA processing promotes cellular transformation.
Figure 2: Impaired miRNA processing promotes tumorigenesis in vivo.
Figure 3: Impaired miRNA processing increases expression of specific oncogenes.
Figure 4: Impaired miRNA processing enhances the in vivo tumor burden in a mouse model of lung cancer.

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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

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 to Tyler Jacks.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Impaired miRNA processing enhances the transformation properties and proliferation of mouse and human cancer cells. (PDF 3370 kb)

Supplementary Fig. 2

Analysis of miRKD mouse lung cancer cell xenografts. (PDF 133 kb)

Supplementary Fig. 3

Impaired miRNA processing does not indiscriminately alter gene expression. (PDF 352 kb)

Supplementary Fig. 4

Enhanced transformation in miRKD cells is specifically due to impaired miRNA processing. (PDF 3066 kb)

Supplementary Fig. 5

Impaired miRNA processing alters miRNA-mediated oncogene expression and cell growth in a cell type–dependent manner. (PDF 2460 kb)

Supplementary Table 1

miRNA profiling data for U2OS, HCA7 and MCF7 cells. (XLS 451 kb)

Supplementary Table 2

Correlation analysis of individual miRNA expression versus cellular transformation. (PDF 41 kb)

Supplementary Methods (PDF 81 kb)

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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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