Nature Genetics
- 38, 1060 - 1065 (2006)
Published online: 30 July 2006; Corrected online: 20 September 2006 | doi:10.1038/ng1855
Augmentation of tumor angiogenesis by a Myc-activated microRNA clusterMichael Dews1, Asal Homayouni1, Duonan Yu1, Danielle Murphy2, Cinzia Sevignani1, Erik Wentzel3, Emma E Furth4, William M Lee2, Greg H Enders2, Joshua T Mendell3 & Andrei Thomas-Tikhonenko11
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. 2
Department of Pathology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. 3
Department of Molecular Biology and Genetics, Johns Hopkins University, Baltimore, Maryland 21205, USA. 4
Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Correspondence should be addressed to Andrei Thomas-Tikhonenko andreit@mail.vet.upenn.edu 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.
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