OncomiR addiction in an in vivo model of microRNA-21-induced pre-B-cell lymphoma

Abstract

MicroRNAs (miRNAs) belong to a recently discovered class of small RNA molecules that regulate gene expression at the post-transcriptional level. miRNAs have crucial functions in the development and establishment of cell identity, and aberrant metabolism or expression of miRNAs has been linked to human diseases, including cancer1. Components of the miRNA machinery and miRNAs themselves are involved in many cellular processes that are altered in cancer, such as differentiation, proliferation and apoptosis. Some miRNAs, referred to as oncomiRs2, show differential expression levels in cancer and are able to affect cellular transformation, carcinogenesis and metastasis, acting either as oncogenes or tumour suppressors. The phenomenon of ‘oncogene addiction’ reveals that despite the multistep nature of tumorigenesis, targeting of certain single oncogenes can have therapeutic value3,4, and the possibility of oncomiR addiction has been proposed but never demonstrated3. MicroRNA-21 (miR-21) is a unique miRNA in that it is overexpressed in most tumour types analysed so far. Despite great interest in miR-21, most of the data implicating it in cancer have been obtained through miRNA profiling and limited in vitro functional assays. To explore the role of miR-21 in cancer in vivo, we used Cre and Tet-off technologies to generate mice conditionally expressing miR-21. Here we show that overexpression of miR-21 leads to a pre-B malignant lymphoid-like phenotype, demonstrating that mir-21 is a genuine oncogene. When miR-21 was inactivated, the tumours regressed completely in a few days, partly as a result of apoptosis. These results demonstrate that tumours can become addicted to oncomiRs and support efforts to treat human cancers through pharmacological inactivation of miRNAs such as miR-21.

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Figure 1: mir-21 LSL-Tetoff transgenic mice overexpress miR-21.
Figure 2: Lymphoma in NesCre8, mir-21 LSL-Tetoff mice.
Figure 3: Tumour dependence on miR-21 overexpression.
Figure 4: Tumour regression is partly due to apoptosis.

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Acknowledgements

We thank X. Liang for help in mouse colony maintenance and genotyping; D. Scavone and T. Nottoli for assistance with generating the transgenic mice; Yale rodent care staff M. Bonk, K. Mclaughlin, J. Graham, D. Clark; C. Zeiss, L. Johnson and G. Terwilliger for help with the necropsy/pathological analysis; and I. Babar, P. Trang and J. Sklar for critical reading of the manuscript. P.P.M. is the recipient of a Postdoctoral Fellowship from Hope Funds for Cancer Research. This work was funded by a grant from the James McDonnell Foundation to F.J.S. and J. B. Weidhaas, and a pilot grant from the Yale Comprehensive Cancer Center.

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F.J.S. designed the project and supervised all the experiments. F.J.S. and M.N. designed the genetically engineered miR-21 mouse. M.N. constructed and tested the mir-21 vector. P.P.M. performed all the phenotyping experiments in the manuscript. F.J.S. and P.P.M. designed the phenotyping experiments and wrote the manuscript.

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Correspondence to Frank J. Slack.

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The authors declare no competing financial interests.

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Supplementary Figures

This file contains Supplementary Figures 1-22 with legends. (PDF 13808 kb)

Supplementary Movie 1

This movie shows NesCre8, mir-21LSL-Tetoff mouse phenotype. Seconds 0-4: The mouse situated at 30° suffers from a conspicuous axillary lymphadenopathy and incipient paraparesis. Seconds 5-7: The mouse situated at 30° suffers from a conspicuous paraparesis. (MOV 8928 kb)

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Medina, P., Nolde, M. & Slack, F. OncomiR addiction in an in vivo model of microRNA-21-induced pre-B-cell lymphoma. Nature 467, 86–90 (2010). https://doi.org/10.1038/nature09284

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