Abstract

The tumor suppressor DAB2IP contributes to modulate the network of information established between cancer cells and tumor microenvironment. Epigenetic and post-transcriptional inactivation of this protein is commonly observed in multiple human malignancies, and can potentially favor progression of tumors driven by a variety of genetic mutations. Performing a high-throughput screening of a large collection of human microRNA mimics, we identified miR-149-3p as a negative post-transcriptional modulator of DAB2IP. By efficiently downregulating DAB2IP, this miRNA enhances cancer cell motility and invasiveness, facilitating activation of NF-kB signaling and promoting expression of pro-inflammatory and pro-angiogenic factors. In addition, we found that miR-149-3p secreted by prostate cancer cells induces DAB2IP downregulation in recipient vascular endothelial cells, stimulating their proliferation and motility, thus potentially remodeling the tumor microenvironment. Finally, we found that inhibition of endogenous miR-149-3p restores DAB2IP activity and efficiently reduces tumor growth and dissemination of malignant cells. These observations suggest that miR-149-3p can promote cancer progression via coordinated inhibition of DAB2IP in tumor cells and in stromal cells.

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Acknowledgements

We thank Giada Pastore (LNCIB, Trieste) for assistance with tissue culture. We thank Andrea Lunardi (CIBIO, University of Trento) for sharing critical reagents. We thank Valeria Capaci, Marco Fantuz, and Lorenzo Bascetta (LNCIB, Trieste) for advice and discussion.

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Author notes

  1. Edited by T. Mak

Affiliations

  1. National Laboratory CIB (LNCIB), AREA Science Park, 34149, Trieste, Italy

    • Arianna Bellazzo
    • , Elena Valentino
    • , Daria Sicari
    • , Federica Serpi
    • , Giannino Del Sal
    •  & Licio Collavin
  2. Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH) Hönggerberg, 8093, Zurich, Switzerland

    • Giulio Di Minin
  3. Department of Life Sciences, University of Trieste, 34127, Trieste, Italy

    • Elena Valentino
    • , Daria Sicari
    • , Roberta Bulla
    • , Giannino Del Sal
    •  & Licio Collavin
  4. Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, BD2K-LINCS DCIC, Mount Sinai Center for Bioinformatics, New York, NY, 10029, USA

    • Denis Torre
  5. Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, 21205, USA

    • Luigi Marchionni
  6. Friedrich Miescher Institute for Biomedical Research, Switzerland and Swiss Institute of Bioinformatics, 4058, Basel, Switzerland

    • Michael B. Stadler
  7. Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126, Torino, Italy

    • Daniela Taverna
  8. Department of Surgery Oncology and Gastroenterology, University of Padova, 35128, Padova, Italy

    • Gaia Zuccolotto
    •  & Antonio Rosato
  9. Istituto Oncologico Veneto IOV-IRCCS, 35128, Padova, Italy

    • Isabella Monia Montagner
    •  & Antonio Rosato
  10. Department of Medical Surgical and Health Sciences, University of Trieste, 34149, Trieste, Italy

    • Federica Tonon
    •  & Cristina Zennaro
  11. Institute for Maternal and Child Health, IRCCS Burlo Garofolo, 34137, Trieste, Italy

    • Chiara Agostinis
  12. Center for Neuroscience and Cell Biology (CNC), University of Coimbra, 3004-504, Coimbra, Portugal

    • Miguel Mano
  13. International Centre for Genetic Engineering and Biotechnology (ICGEB), 34149, Trieste, Italy

    • Miguel Mano

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The authors declare that they have no conflict of interest.

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Correspondence to Giannino Del Sal or Licio Collavin.

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DOI

https://doi.org/10.1038/s41418-018-0088-5