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Efficient in vivo microRNA targeting of liver metastasis

Oncogene volume 30, pages 1481–1488 (2011)Cite this article

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Abstract

Targeting oncogenic microRNAs (miRNAs) is emerging as a promising strategy for cancer therapy. In this study, we provide proof of principle for the safety and efficacy of miRNA targeting against metastatic tumors. We tested the impact of targeting miR-182, a pro-metastatic miRNA frequently overexpressed in melanoma, the in vitro silencing of which represses invasion and induces apoptosis. Specifically, we assessed the effect of anti-miR-182 oligonucleotides synthesized with 2′ sugar modifications and a phosphorothioate backbone in a mouse model of melanoma liver metastasis. Luciferase imaging showed that mice treated with anti-miR-182 had a lower burden of liver metastases compared with control. We confirmed that miR-182 levels were effectively downregulated in the tumors of anti-miR-treated mice compared with tumors of control-treated mice, both in the liver and in the spleen. This effect was accompanied by an upregulation of multiple miR-182 direct targets. Transcriptional profiling of tumors treated with anti-miR-182 or with control oligonucleotides revealed an enrichment of genes controlling survival, adhesion and migration modulated in response to anti-miR-182 treatment. These data indicate that in vivo administration of anti-miRs allows for efficient miRNA targeting and concomitant upregulation of miRNA-controlled genes. Our results demonstrate that the use of anti-miR-182 is a promising therapeutic strategy for metastatic melanoma and provide a solid basis for testing similar strategies in human metastatic tumors.

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Acknowledgements

We thank members of the NYU Cancer Institute Genomics Facility for array profiling. We are grateful to Dr Cindy Loomis and members of the NYU Histopathology (Tim Macatee) and the Immunohistochemistry Core Laboratories for tissue processing and histological staining, and to Dr Elisa de Stanchina (MSKCC Antitumor Assessment core facility) for mouse blood work. This work was funded by the ConCerN foundation and the Harry Lloyd Charitable Trust. CH is supported by the NYU Physician Scientist Training Program, National Cancer Center Postdoctoral fellowship and the NIH T32 CA09454-19 fellowship training grant. MFS by a National Cancer Center Postdoctoral fellowship.

Author contributions: CH, MFS, SM, EM and EH designed, and CH, MFS, SM, AG-S, BL, LC and EH performed the experiments; CH, MFS, AG-S, FD, JZ, EM and EH analyzed data; BL and DM assisted with the use of the IVIS equipment; CH, MFS, AG-S, IO, EM and EH wrote the paper.

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Authors and Affiliations

  1. Department of Pathology, NYU School of Medicine, New York, NY, USA

    C Huynh, M F Segura, A Gaziel-Sovran, S Menendez, F Darvishian, L Chiriboga, B Levin, D Meruelo, J Zavadil & E Hernando

  2. Department of Medicine, NYU School of Medicine, New York, NY, USA

    C Huynh

  3. Department of Dermatology, NYU School of Medicine, New York, NY, USA

    I Osman

  4. NYU Center for Health Informatics and Bioinformatics, NYU School of Medicine, New York, NY, USA

    J Zavadil

  5. Interdisciplinary Melanoma Cooperative Group, NYU School of Medicine, New York, NY, USA

    C Huynh, M F Segura, A Gaziel-Sovran, S Menendez, F Darvishian, L Chiriboga, I Osman & E Hernando

  6. Regulus Therapeutics, Inc., San Diego, CA, USA

    E G Marcusson

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Correspondence to E Hernando.

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EGM is an employee and shareholder of Regulus Therapeutics. All other authors declare no conflict of interest.

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Huynh, C., Segura, M., Gaziel-Sovran, A. et al. Efficient in vivo microRNA targeting of liver metastasis. Oncogene 30, 1481–1488 (2011). https://doi.org/10.1038/onc.2010.523

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