Systemic miRNA-7 delivery inhibits tumor angiogenesis and growth in murine xenograft glioblastoma

N. Babae, M. Bourajjaj, Y. Liu, J.R. Beijnum, F. Cerisoli, P.V. Scaria, Mark Verheul, M.P. Berkel, E.H. Pieters, R.J. van Haastert, A. Yousefi, E. Mastrobattista, Gerrit Storm, E. Berezikov, E. Cuppen, M. Woodle, R.Q.J. Schaapveld, G.P. Prevost, A.W. Griffioen, P.I. NoortR.M. Schiffelers

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Abstract

Tumor-angiogenesis is the multi-factorial process of sprouting of endothelial cells (EC) into micro-vessels to provide tumor cells with nutrients and oxygen. To explore miRNAs as therapeutic angiogenesis-inhibitors, we performed a functional screen to identify miRNAs that are able to decrease EC viability. We identified miRNA-7 (miR-7) as a potent negative regulator of angiogenesis. Introduction of miR-7 in EC resulted in strongly reduced cell viability, tube formation, sprouting and migration. Application of miR-7 in the chick chorioallantoic membrane assay led to a profound reduction of vascularization, similar to anti-angiogenic drug sunitinib. Local administration of miR-7 in an in vivo murine neuroblastoma tumor model significantly inhibited angiogenesis and tumor growth. Finally, systemic administration of miR-7 using a novel integrin-targeted biodegradable polymeric nanoparticles that targets both EC and tumor cells, strongly reduced angiogenesis and tumor proliferation in mice with human glioblastoma xenografts. Transcriptome analysis of miR-7 transfected EC in combination with in silico target prediction resulted in the identification of OGT as novel target gene of miR-7. Our study provides a comprehensive validation of miR-7 as novel anti-angiogenic therapeutic miRNA that can be systemically delivered to both EC and tumor cells and offers promise for miR-7 as novel anti-tumor therapeutic.
Original languageUndefined
Pages (from-to)6687-6700
JournalOncotarget
Volume5
Issue number16
DOIs
Publication statusPublished - 2014

Keywords

  • IR-95146
  • METIS-309475

Cite this

Babae, N., Bourajjaj, M., Liu, Y., Beijnum, J. R., Cerisoli, F., Scaria, P. V., ... Schiffelers, R. M. (2014). Systemic miRNA-7 delivery inhibits tumor angiogenesis and growth in murine xenograft glioblastoma. Oncotarget, 5(16), 6687-6700. https://doi.org/10.18632/oncotarget.2235