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Inhibition of miR-9 de-represses HuR and DICER1 and impairs Hodgkin lymphoma tumour outgrowth in vivo

Oncogene volume 31, pages 5081–5089 (2012)Cite this article

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Abstract

MicroRNAs are important regulators of gene expression in normal development and disease. miR-9 is overexpressed in several cancer forms, including brain tumours, hepatocellular carcinomas, breast cancer and Hodgkin lymphoma (HL). Here we demonstrated a relevance for miR-9 in HL pathogenesis and identified two new targets Dicer1 and HuR. HL is characterized by a massive infiltration of immune cells and fibroblasts in the tumour, whereas malignant cells represent only 1% of the tumour mass. These infiltrates provide important survival and growth signals to the tumour cells, and several lines of evidence indicate that they are essential for the persistence of HL. We show that inhibition of miR-9 leads to derepression of DICER and HuR, which in turn results in a decrease in cytokine production by HL cells followed by an impaired ability to attract normal inflammatory cells. Finally, inhibition of miR-9 by a systemically delivered antimiR-9 in a xenograft model of HL increases the protein levels of HuR and DICER1 and results in decreased tumour outgrowth, confirming that miR-9 actively participates in HL pathogenesis and points to miR-9 as a potential therapeutic target.

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Acknowledgements

This work was supported by The Danish National Advanced Technology Foundation, The EC FP7 ONCOMIRS consortium (Grant agreement number 201102: this publication reflects only authors' views;the commission is not liable for any use that may be made of the information herein), The Novo Nordisk Foundation, The Lundbeck Foundation, The Danish Cancer Society and the Danish National Research Foundation. Dr Bellan's and Professor Leoncini's work is supported by the Monte dei Paschi di Siena Foundation. Dr Leucci is supported by a grant from the Danish Medical Research Council.

Author contributions: EL and AHL designed the overall study. SO and SK designed and provided the tiny anti-miR-LNAs. LHG performed all the bioinformatic analyses. LL and CB performed the analysis on NOG MICE. KTJ coordinated the mouse experiments; AZ and EL performed all the experiments. EL and AHL wrote the paper.

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Author notes

  1. L H Gregersen

    Present address: 6Current address: Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany,

  2. A Zriwil, L H Gregersen and K T Jensen: These authors contributed equally to the work

Authors and Affiliations

  1. Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark

    E Leucci, A Zriwil, L H Gregersen, K T Jensen & A H Lund

  2. Santaris Pharma, Hørsholm, Denmark

    S Obad & S Kauppinen

  3. Department of Human Pathology and Oncology, University of Siena, Siena, Italy

    C Bellan & L Leoncini

  4. Copenhagen Institute of Technology, Aalborg University, Ballerup, Denmark

    S Kauppinen

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Correspondence to A H Lund.

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Dr Obad and Professor Kauppinen are employees of Santaris Pharma. The other authors declare no conflict of interest.

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Leucci, E., Zriwil, A., Gregersen, L. et al. Inhibition of miR-9 de-represses HuR and DICER1 and impairs Hodgkin lymphoma tumour outgrowth in vivo. Oncogene 31, 5081–5089 (2012). https://doi.org/10.1038/onc.2012.15

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