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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We are indebted to C. Dang (Johns Hopkins University) for fostering collaborations between the investigators. We are grateful to C. Simon and C.-J. Hu (University of Pennsylvania) for providing HIF1α-overexpressing cell lysates for protein blot analysis and J. Tobias (University of Pennsylvania) for his help with microarray data analysis. We thank W. El-Deiry, A. Rustgi, and S. Fuchs (University of Pennsylvania) for stimulating discussions and comments on the manuscript. M. Goldschmidt and J. Burns (University of Pennsylvania) are acknowledged for their help with histopathological analyses. This work was supported by US National Institutes of Health grants CA 097932 and DK 050306 and a University of Pennsylvania Research Foundation grant to A.T.-T.
The authors declare no competing financial interests.
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Dews, M., Homayouni, A., Yu, D. et al. Augmentation of tumor angiogenesis by a Myc-activated microRNA cluster. Nat Genet 38, 1060–1065 (2006). https://doi.org/10.1038/ng1855
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