Augmentation of tumor angiogenesis by a Myc-activated microRNA cluster

Michael Dews, Asal Homayouni, Duonan Yu, Danielle Murphy, Cinzia Sevignani, Erik Wentzel, Emma E. Furth, William M. Lee, Greg H. Enders, Joshua T. Mendell, Andrei Thomas-Tikhonenko

Research output: Contribution to journalArticle

840 Scopus citations

Abstract

Human adenocarcinomas commonly harbor mutations in the KRAS and MYC proto-oncogenes and the TP53 tumor suppressor gene. All three genetic lesions are potentially pro-angiogenic, as they sustain production of vascular endothelial growth factor (VEGF). Yet Kras-transformed mouse colonocytes lacking p53 formed indolent, poorly vascularized tumors, whereas additional transduction with a Myc-encoding retrovirus promoted vigorous vascularization and growth. In addition, VEGF levels were unaffected by Myc, but enhanced neovascularization correlated with downregulation of anti-angiogenic thrombospondin-1 (Tsp1) and related proteins, such as connective tissue growth factor (CTGF). Both Tsp1 and CTGF are predicted targets for repression by the miR-17-92 microRNA cluster, which was upregulated in colonocytes coexpressing K-Ras and c-Myc. Indeed, miR-17-92 knockdown with antisense 2′-O-methyl oligoribonucleotides partly restored Tsp1 and CTGF expression; in addition, transduction of Ras-only cells with a miR-17-92-encoding retrovirus reduced Tsp1 and CTGF levels. Notably, miR-17-92-transduced cells formed larger, better-perfused tumors. These findings establish a role for microRNAs in non-cell-autonomous Myc-induced tumor phenotypes.

Original languageEnglish (US)
Pages (from-to)1060-1065
Number of pages6
JournalNature genetics
Volume38
Issue number9
DOIs
StatePublished - Sep 4 2006

ASJC Scopus subject areas

  • Genetics

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    Dews, M., Homayouni, A., Yu, D., Murphy, D., Sevignani, C., Wentzel, E., Furth, E. E., Lee, W. M., Enders, G. H., Mendell, J. T., & Thomas-Tikhonenko, A. (2006). Augmentation of tumor angiogenesis by a Myc-activated microRNA cluster. Nature genetics, 38(9), 1060-1065. https://doi.org/10.1038/ng1855