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

Negar Babae, Meriem Bourajjaj, Yijia Liu, Judy R Van Beijnum, Francesco Cerisoli, Puthupparampil V Scaria, Mark Verheul, Maaike P Van Berkel, Ebel H E Pieters, Rick J Van Haastert, Afrouz Yousefi, Enrico Mastrobattista, Gert Storm, Eugene Berezikov, Edwin Cuppen, Martin Woodle, Roel Q J Schaapveld, Gregoire P Prevost, Arjan W Griffioen, Paula I Van NoortRaymond M Schiffelers

Research output: Contribution to journal/periodicalArticleScientificpeer-review

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 languageEnglish
Pages (from-to)6687-700
Number of pages14
JournalOncotarget
Volume5
Issue number16
Publication statusPublished - 30 Aug 2014

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