Cell-autonomous and cell non-autonomous downregulation of tumor suppressor DAB2IP by microRNA-149-3p promotes aggressiveness of cancer cells

A. Bellazzo, G. Di Minin, E. Valentino, D. Sicari, D. Torre, L. Marchionni, F. Serpi, M.B. Stadler, D. Taverna, G. Zuccolotto, I.M. Montagner, A. Rosato, F. Tonon, C. Zennaro, C. Agostinis, R. Bulla, M. Mano, G. Del Sal, L. Collavin

Research output: Contribution to journalArticle

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. © 2018 ADMC Associazione Differenziamento e Morte Cellulare.
Original languageEnglish
Pages (from-to)1224-1238
Number of pages15
JournalCell Death and Differentiation
Volume25
Issue number7
DOIs
Publication statusPublished - Jul 1 2018

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Keywords

  • disabled 2 interacting protein
  • microRNA
  • microRNA 149 3p
  • RNA
  • tumor suppressor protein
  • unclassified drug, animal experiment
  • animal model
  • animal tissue
  • Article
  • cancer cell
  • cancer cell culture
  • cell invasion
  • cell motility
  • cell proliferation
  • controlled study
  • down regulation
  • embryo
  • female
  • gene expression
  • high throughput screening
  • human
  • human cell
  • metastasis
  • mouse
  • nonhuman
  • priority journal
  • prostate cancer
  • protein expression
  • signal transduction
  • tumor growth
  • tumor microenvironment
  • tumor xenograft
  • vascular endothelial cell
  • zebra fish

Cite this

Bellazzo, A., Di Minin, G., Valentino, E., Sicari, D., Torre, D., Marchionni, L., Serpi, F., Stadler, M. B., Taverna, D., Zuccolotto, G., Montagner, I. M., Rosato, A., Tonon, F., Zennaro, C., Agostinis, C., Bulla, R., Mano, M., Del Sal, G., & Collavin, L. (2018). Cell-autonomous and cell non-autonomous downregulation of tumor suppressor DAB2IP by microRNA-149-3p promotes aggressiveness of cancer cells. Cell Death and Differentiation, 25(7), 1224-1238. https://doi.org/10.1038/s41418-018-0088-5