Transcription profiling of mouse colon carcinomas over-expressing c-Myc

ABSTRACT: MycRas vs Ras colon carcinoma. Human adenocarcinomas commonly harbor mutations in the Ki-Ras and c-Myc proto-oncogenes and the trp53 tumor suppressor gene. All three genetic lesions are potentially pro-angiogenic, since they sustain production of the vascular endothelial growth factor (VEGF). Yet murine Ki-Ras/p53-null colonocytes formed indolent, poorly vascularized tumors, whereas additional transduction with a Myc-encoding retrovirus promoted vigorous vascularization and growth. While VEGF levels were unaffected by Myc, enhanced neovascularization correlated with down-regulation 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 RasMyc colonocytes. Indeed, miR-17-92 knock-down with antisense 2’-O-methyl oligoribonucleotides partly restored Tsp1 and CTGF expression, and conversely, transduction of Ras-only cells with a miR-17-92-encoding retrovirus reduced Tsp1 and CTGF levels. Importantly, 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.

ORGANISM(S): Mus musculus

SUBMITTER: Andrei Thomas-Tikhonenko 

PROVIDER: E-MEXP-757 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress