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Post-transcriptional gene regulation by HuR promotes a more tumorigenic phenotype

Oncogene volume 27, pages 6151–6163 (2008)Cite this article

Abstract

In a breast tumor xenograft model, the MCT-1 oncogene increases the in vivo tumorgenicity of MCF7 cells by promoting angiogenesis and inhibiting apoptosis. Increases in the tumor microvascular density are accompanied by a strong reduction in the levels of the angiogenesis inhibitor thrombospondin-1 (TSP1), but the mechanisms underlying this process are unknown. We show that TSP1 expression is controlled, at least in part, by post-transcriptional events. Using RNA interference to knock down the expression of the RNA-binding protein HuR in MCF7 cells as well as HuR overexpression, we demonstrate that HuR plays an important role in translation of the TSP1 mRNA. Furthermore, employing the RIP-Chip assay yielded 595 transcripts with significantly altered binding to HuR in the more tumorigenic breast cancer clones compared with the weakly tumorigenic clones. These mRNAs clustered in several pathways implicated in the transformed phenotype, such as the RAS pathway (involved in mitogenesis), the PI3K pathway (evasion of apoptosis) and pathways mediating angiogenesis and the cellular response to hypoxia. These findings demonstrate for the first time that global changes in HuR-bound mRNAs are implicated in the evolution to a more tumorigenic phenotype in an in vivo tumor model and underscore the role of global mRNA-protein interactions toward tumor progression.

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Acknowledgements

We thank Dr Y Zhang for assistance with the statistical analysis of the RIP-Chip array data and Dr J Hasday for technical support. A Merit Review Award from the Department of Veterans Affairs to RBG supported this work. MG and SS were supported by the National Institute on Aging Intramural Research Program, NIH.

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Authors and Affiliations

  1. Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore, MD, USA

    K Mazan-Mamczarz, P R Hagner, S Corl & R B Gartenhaus

  2. Laboratory of Cellular and Molecular Biology, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA

    S Srikantan & M Gorospe

  3. Gene Expression and Genomics Unit, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA

    W H Wood & K G Becker

  4. Department of Molecular Genetics & Microbiology, Duke University Medical Center, Durham, NC, USA

    J D Keene

  5. Department of Urology and Robert H Lurie Comprehensive Cancer Center, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA

    A S Levenson

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  1. K Mazan-Mamczarz
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Correspondence to R B Gartenhaus.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Mazan-Mamczarz, K., Hagner, P., Corl, S. et al. Post-transcriptional gene regulation by HuR promotes a more tumorigenic phenotype. Oncogene 27, 6151–6163 (2008). https://doi.org/10.1038/onc.2008.215

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