1. Augmentation of tumor angiogenesis by a Myc-activated microRNA cluster.
- Author
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Dews M, Homayouni A, Yu D, Murphy D, Sevignani C, Wentzel E, Furth EE, Lee WM, Enders GH, Mendell JT, and Thomas-Tikhonenko A
- Subjects
- Animals, Cell Line, Cell Line, Transformed, Cell Transformation, Viral, Cells, Cultured, Connective Tissue Growth Factor, Culture Media, Conditioned analysis, Gene Expression Regulation, Neoplastic, Genetic Vectors, Humans, Immediate-Early Proteins genetics, Immediate-Early Proteins metabolism, In Vitro Techniques, Intercellular Signaling Peptides and Proteins genetics, Intercellular Signaling Peptides and Proteins metabolism, Mice, Mice, Inbred C57BL, Neoplasms pathology, Neovascularization, Pathologic genetics, Oligonucleotides, Antisense pharmacology, Proto-Oncogene Proteins c-myc genetics, RNA, Neoplasm metabolism, Retroviridae genetics, Stem Cells cytology, Thrombospondin 1 genetics, Thrombospondin 1 metabolism, Transplantation, Homologous, Vascular Endothelial Growth Factor A analysis, Vascular Endothelial Growth Factor A metabolism, MicroRNAs metabolism, Neoplasms blood supply, Neovascularization, Pathologic metabolism, Proto-Oncogene Proteins c-myc physiology
- 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.
- Published
- 2006
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