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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Bartel, D.P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004).
Gregory, R.I. & Shiekhattar, R. MicroRNA biogenesis and cancer. Cancer Res. 65, 3509–3512 (2005).
Lu, J. et al. MicroRNA expression profiles classify human cancers. Nature 435, 834–838 (2005).
Wislez, M. et al. High expression of ligands for chemokine receptor CXCR2 in alveolar epithelial neoplasia induced by oncogenic kras. Cancer Res. 66, 4198–4207 (2006).
Johnson, L. et al. Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature 410, 1111–1116 (2001).
Harfe, B.D., McManus, M.T., Mansfield, J.H., Hornstein, E. & Tabin, C.J. The RNaseIII enzyme Dicer is required for morphogenesis but not patterning of the vertebrate limb. Proc. Natl. Acad. Sci. USA 102, 10898–10903 (2005).
Kanellopoulou, C. et al. Dicer-deficient mouse embryonic stem cells are defective in differentiation and centromeric silencing. Genes Dev. 19, 489–501 (2005).
Murchison, E.P., Partridge, J.F., Tam, O.H., Cheloufi, S. & Hannon, G.J. Characterization of Dicer-deficient murine embryonic stem cells. Proc. Natl. Acad. Sci. USA 102, 12135–12140 (2005).
Ventura, A. et al. Cre-lox-regulated conditional RNA interference from transgenes. Proc. Natl. Acad. Sci. USA 101, 10380–10385 (2004).
Tuveson, D.A. et al. Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell 5, 375–387 (2004).
Adhikary, S. & Eilers, M. Transcriptional regulation and transformation by Myc proteins. Nat. Rev. Mol. Cell Biol. 6, 635–645 (2005).
John, B. et al. Human MicroRNA targets. PLoS Biol. 2, e363 (2004).
Johnson, S.M. et al. RAS is regulated by the let-7 microRNA family. Cell 120, 635–647 (2005).
Jackson, E.L. et al. Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Genes Dev. 15, 3243–3248 (2001).
Karube, Y. et al. Reduced expression of Dicer associated with poor prognosis in lung cancer patients. Cancer Sci. 96, 111–115 (2005).
Hayashita, Y. et al. A polycistronic microRNA cluster, miR-17–92, is overexpressed in human lung cancers and enhances cell proliferation. Cancer Res. 65, 9628–9632 (2005).
He, L. et al. A microRNA polycistron as a potential human oncogene. Nature 435, 828–833 (2005).
O'Donnell, K.A., Wentzel, E.A., Zeller, K.I., Dang, C.V. & Mendell, J.T. c-Myc-regulated microRNAs modulate E2F1 expression. Nature 435, 839–843 (2005).
Ota, A. et al. Identification and characterization of a novel gene, C13orf25, as a target for 13q31-q32 amplification in malignant lymphoma. Cancer Res. 64, 3087–3095 (2004).
Volinia, S. et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc. Natl. Acad. Sci. USA 103, 2257–2261 (2006).
Thomson, J.M. et al. Extensive post-transcriptional regulation of microRNAs and its implications for cancer. Genes Dev. 20, 2202–2207 (2006).
Sage, J. et al. Targeted disruption of the three Rb-related genes leads to loss of G(1) control and immortalization. Genes Dev. 14, 3037–3050 (2000).
Brummelkamp, T.R., Bernards, R. & Agami, R. A system for stable expression of short interfering RNAs in mammalian cells. Science 296, 550–553 (2002).
Sweet-Cordero, A. et al. An oncogenic KRAS2 expression signature identified by cross-species gene-expression analysis. Nat. Genet. 37, 48–55 (2005).
Martens, J.H. et al. The profile of repeat-associated histone lysine methylation states in the mouse epigenome. EMBO J. 24, 800–812 (2005).
Hutvagner, G., Simard, M.J., Mello, C.C. & Zamore, P.D. Sequence-specific inhibition of small RNA function. PLoS Biol. 2, E98 (2004).
Meister, G., Landthaler, M., Dorsett, Y. & Tuschl, T. Sequence-specific inhibition of microRNA- and siRNA-induced RNA silencing. RNA 10, 544–550 (2004).
Doench, J.G., Petersen, C.P. & Sharp, P.A. siRNAs can function as miRNAs. Genes Dev. 17, 438–442 (2003).
Jackson, E.L. et al. The differential effects of mutant p53 alleles on advanced murine lung cancer. Cancer Res. 65, 10280–10288 (2005).
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.
Author information
Authors and Affiliations
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.
Corresponding author
Ethics declarations
Competing interests
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)
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ng2003
This article is cited by
-
The evolution of preclinical models for myelodysplastic neoplasms
Leukemia (2024)
-
The miR-9-5p/KLF5/IL-1β Axis Regulates Airway Smooth Muscle Cell Proliferation and Apoptosis to Aggravate Airway Remodeling and Inflammation in Asthma
Biochemical Genetics (2024)
-
Hallmark discoveries in the biology of Wilms tumour
Nature Reviews Urology (2024)
-
MSI2 promotes translation of multiple IRES-containing oncogenes and virus to induce self-renewal of tumor initiating stem-like cells
Cell Death Discovery (2023)
-
Targeting Novel microRNAs in Developing Novel Alzheimer's Disease Treatments
Neurochemical Research (2023)