Augmentation of tumor angiogenesis by a Myc-activated microRNA cluster.
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.
Dews
Michael
M
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Homayouni
Asal
A
Yu
Duonan
D
Murphy
Danielle
D
Sevignani
Cinzia
C
Wentzel
Erik
E
Furth
Emma E
EE
Lee
William M
WM
Enders
Greg H
GH
Mendell
Joshua T
JT
Thomas-Tikhonenko
Andrei
A
D000818:Animals; D002460:Cell Line; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor; D017077:Culture Media, Conditioned / Q000032:analysis; D015972:Gene Expression Regulation, Neoplastic; D005822:Genetic Vectors; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D066298:In Vitro Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D009369:Neoplasms / Q000098:blood supply* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000502:physiology*; D012334:RNA, Neoplasm / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D013234:Stem Cells / Q000166:cytology; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism; D014184:Transplantation, Homologous; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000378:metabolism
C526317:CCN2 protein, human; C526318:CCN2 protein, mouse; D017077:Culture Media, Conditioned; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D035683:MicroRNAs; D016376:Oligonucleotides, Antisense; D016271:Proto-Oncogene Proteins c-myc; D012334:RNA, Neoplasm; D019700:Thrombospondin 1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D055513:Connective Tissue Growth Factor