Augmentation of tumor angiogenesis by a Myc-activated microRNA cluster

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.

The regulatory role of microRNAs in angiogenesis‐related diseases

“…The miR‐17‐92 gene cluster includes miR‐17‐5p, miR‐17‐3p, miR‐18a, miR‐19a, miR‐20a, miR‐19b and miR‐92a, which exhibits miscellaneous biological functions in angiogenesis 80, 81. Studies have shown that miR‐18 and miR‐19 promote tumour angiogenesis by reducing connective tissue growth factor (CTGF) and thrombin sensitive protein 1 (Tsp1) and increasing VEGF 51, 80, 81.…”

Tumor-suppressive microRNA-22 inhibits the transcription of E-box-containing c-Myc target genes by silencing c-Myc binding protein

“…It is not fully established how MYCBP regulates these E-box-containing genes because of growing evidence about the function of MYCBP (Furusawa et al, 2001Yukitake et al, 2002;Ishizaki et al, 2006), but there is evidence suggesting that MYCBP acts, at least in part, through modulating the transactivation activity of c-Myc to enhance the transcription of these genes (Taira et al, 1998;Sakamuro and Prendergast, 1999). Recent studies showed that some c-Myc-mediated miRNAs were implicated in tumorigenesis, embryonic stem cell differentiation and glutamine metabolism (He et al, 2005;O'Donnell et al, 2005;Dews et al, 2006;Chang et al, 2008;Sander et al, 2008;Gao et al, 2009;Lin et al, 2009;Mestdagh et al, 2009). However, only two miRNAs were found to modulate c-Myc, whereas c-Myc is not their significant targets (Sampson et al, 2007;Lal et al, 2009).…”

Genetic variants within miR-126 and miR-335 are not associated with breast cancer risk

“…At the primary PCR step, DNA was amplified under following conditions: 95 ºC for 2 min, 8 The Hardy-Weinberg equilibrium [32] test was applied using the chi-square 'goodness-of-fit' test offered as a tool by the Institute of Human Genetics, Technical University Munich, Munich, Germany (http://ihg.gsf.de/cgi-bin/hw/hwa1.pl). Genotype-specific odds ratios (OR), 95 % confidence intervals (CI) and P values were computed by unconditional logistic regression with SAS version 9.1 (SAS Institute Inc., Cary, NC).…”

“…A single miRNA can repress the expression of hundreds of proteins [3]. MiRNAs are involved in the regulation of several cellular pathways including pathways important for cancer development such as immune system regulation, haematopoiesis, angiogenesis, cell proliferation, differentiation and apoptosis [4][5][6][7][8][9]. Elevated or decreased expression of miRNAs has been found in various tumor types including breast cancer [10,11].…”