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.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line
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Cell Line, Transformed
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Cell Transformation, Viral
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Cells, Cultured
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Connective Tissue Growth Factor
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Culture Media, Conditioned / analysis
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Gene Expression Regulation, Neoplastic
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Genetic Vectors
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Humans
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Immediate-Early Proteins / genetics
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Immediate-Early Proteins / metabolism
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In Vitro Techniques
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism
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Mice
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Mice, Inbred C57BL
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MicroRNAs / metabolism*
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Neoplasms / blood supply*
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Neoplasms / pathology
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Neovascularization, Pathologic / genetics
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Neovascularization, Pathologic / metabolism*
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Oligonucleotides, Antisense / pharmacology
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Proto-Oncogene Proteins c-myc / genetics
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Proto-Oncogene Proteins c-myc / physiology*
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RNA, Neoplasm / metabolism
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Retroviridae / genetics
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Stem Cells / cytology
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Thrombospondin 1 / genetics
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Thrombospondin 1 / metabolism
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Transplantation, Homologous
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Vascular Endothelial Growth Factor A / analysis
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Vascular Endothelial Growth Factor A / metabolism
Substances
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CCN2 protein, human
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CCN2 protein, mouse
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Culture Media, Conditioned
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Immediate-Early Proteins
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Intercellular Signaling Peptides and Proteins
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MicroRNAs
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Oligonucleotides, Antisense
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Proto-Oncogene Proteins c-myc
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RNA, Neoplasm
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Thrombospondin 1
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VEGFA protein, human
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Vascular Endothelial Growth Factor A
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Connective Tissue Growth Factor