1. Augmentation of tumor angiogenesis by a Myc-activated microRNA cluster.
- Author
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Dews, Michael, Homayouni, Asal, Yu, Duonan, Murphy, Danielle, Sevignani, Cinzia, Wentzel, Erik, Furth, Emma E., Lee, William M., Enders, Greg H., Mendell, Joshua T., and Thomas-Tikhonenko, Andrei
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ADENOCARCINOMA , *NEOVASCULARIZATION inhibitors , *GENETIC mutation , *TUMOR suppressor genes , *VASCULAR endothelial growth factors , *GENETIC research - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2006
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