Augmentation of tumor angiogenesis by a Myc-activated microRNA cluster

Michael Dews, Asal Homayouni, Duonan Yu, Danielle Murphy, Cinzia Sevignani, Erik Wentzel, Emma E. Furth, William M. Lee, Greg H. Enders, Joshua T. Mendell, Andrei Thomas-Tikhonenko

Research output: Contribution to journalArticle

829 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1060-1065
Number of pages6
JournalNature Genetics
Volume38
Issue number9
DOIs
StatePublished - Sep 4 2006

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Thrombospondin 1
Connective Tissue Growth Factor
MicroRNAs
Retroviridae
Vascular Endothelial Growth Factor A
Neoplasms
Oligoribonucleotides
Proto-Oncogenes
Tumor Suppressor Genes
Adenocarcinoma
Down-Regulation
Phenotype
Mutation
Growth
Proteins

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Dews, M., Homayouni, A., Yu, D., Murphy, D., Sevignani, C., Wentzel, E., ... Thomas-Tikhonenko, A. (2006). Augmentation of tumor angiogenesis by a Myc-activated microRNA cluster. Nature Genetics, 38(9), 1060-1065. https://doi.org/10.1038/ng1855

Augmentation of tumor angiogenesis by a Myc-activated microRNA cluster. / Dews, Michael; Homayouni, Asal; Yu, Duonan; Murphy, Danielle; Sevignani, Cinzia; Wentzel, Erik; Furth, Emma E.; Lee, William M.; Enders, Greg H.; Mendell, Joshua T.; Thomas-Tikhonenko, Andrei.

In: Nature Genetics, Vol. 38, No. 9, 04.09.2006, p. 1060-1065.

Research output: Contribution to journalArticle

Dews, M, Homayouni, A, Yu, D, Murphy, D, Sevignani, C, Wentzel, E, Furth, EE, Lee, WM, Enders, GH, Mendell, JT & Thomas-Tikhonenko, A 2006, 'Augmentation of tumor angiogenesis by a Myc-activated microRNA cluster', Nature Genetics, vol. 38, no. 9, pp. 1060-1065. https://doi.org/10.1038/ng1855
Dews M, Homayouni A, Yu D, Murphy D, Sevignani C, Wentzel E et al. Augmentation of tumor angiogenesis by a Myc-activated microRNA cluster. Nature Genetics. 2006 Sep 4;38(9):1060-1065. https://doi.org/10.1038/ng1855
Dews, Michael ; Homayouni, Asal ; Yu, Duonan ; Murphy, Danielle ; Sevignani, Cinzia ; Wentzel, Erik ; Furth, Emma E. ; Lee, William M. ; Enders, Greg H. ; Mendell, Joshua T. ; Thomas-Tikhonenko, Andrei. / Augmentation of tumor angiogenesis by a Myc-activated microRNA cluster. In: Nature Genetics. 2006 ; Vol. 38, No. 9. pp. 1060-1065.
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