Control of Vascular Cell Differentiation by Homeobox Transcription Factors

Gorski, David H.

doi:10.1016/s1050-1738(03)00081-1

Cited by 65 publications

(52 citation statements)

References 60 publications

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“…However, we found that the methylation status of RASSF1A was not related to age, grade, stage, histological type, ascites, and CA125, which was similar to the results of Bhagat et al (2012). Homeodomain-containing genes encode transcriptional factors that function during embryonic development to control patterning, differentiation, and proliferation (Gorski and Walsh, 2003). A study by Montavon et al (2012) found a 95% frequency of methylation of HOXA9 in high-grade serous ovary cancer, as HOXA9 regulates serous differentiation of the Müllerian ducts to Fallopian tubes (Du and Taylor, 2004;Chen et al, 2005) and HOXA9 methylation in ovarian cancer may reflect a loss of transcriptional plasticity during disease development and a shift towards epithelial cell dedifferentiation or high-grade classification (Coolon et al, 2010).…”

Section: Discussionsupporting

confidence: 62%

Cumulative methylation alternations of gene promoters and protein markers for diagnosis of epithelial ovarian cancer

Xing¹,

Tang

et al. 2015

Genet. Mol. Res.

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ABSTRACT. DNA methylation plays an important role in carcinogenesis and cancer development. In this study, we examined gene methylation in epithelial ovarian cancer (EOC) using cationic conjugated polymer (CCP)-based fluorescence resonance energy transfer (FRET) to evaluate the application of cumulative methylation alternations of genes associated with cancer antigen 125 for early cancer diagnosis. The methylation status of 3 genes (Ras association domain family 1 isoform A, RASSF1A; opioid-binding protein/cell adhesion molecule, OPCML; homeobox A9, HOXA9) were examined and compared in 35 EOC samples and 11 normal ovarian tissue samples using CCP-based FRET. Gene methylation levels were clustered into 3 sections and assigned a value; values for the 3 genes were summed. Although methylation of the OPCML gene was significantly associated with stage, histological types, grade, and ascites and that of RASSF1A and HOXA9 was not, the sum for the 3 genes was significantly associated with stage and ascites. The sum showed higher sensitivity (85.7%) and specificity (100%) for discriminating EOC from normal ovarian tissues than did the methylation status of RASSF1A, OPCML, and HOXA9

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Section: Discussionsupporting

confidence: 62%

Cumulative methylation alternations of gene promoters and protein markers for diagnosis of epithelial ovarian cancer

Xing¹,

Tang

et al. 2015

Genet. Mol. Res.

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“…Indeed, several homeobox genes (HOXA9EC, HOXB3, HOXB5, HOXD3, HOXD10, and Hex) have already been implicated in this process (7,43). We postulated that at least one additional homeobox gene, Gax, is also likely to play an important role in regulating endothelial cell angiogenesis.…”

Section: Discussionmentioning

confidence: 95%

“…Because of their ubiquitous role as regulators of cellular differentiation and body plan formation during embryogenesis, as well as oncogenes and tumor suppressors in various human cancers (5,6), it is not surprising that homeobox genes have been implicated in regulating the phenotypic changes that endothelial cells undergo during angiogenesis (7). In particular, one diverged homeobox gene, Gax (whose mouse homologue is known as Meox-2), has several characteristics that suggest that it may play an important role as an inhibitor of the endothelial cell phenotypic changes that occur in response to stimulation by proangiogenic or proinflammatory factors (8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

The Homeobox Gene Gax Inhibits Angiogenesis through Inhibition of Nuclear Factor-κB–Dependent Endothelial Cell Gene Expression

2005

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The growth and metastasis of tumors are heavily dependent on angiogenesis, but much of the transcriptional regulation of vascular endothelial cell gene expression responsible for angiogenesis remains to be elucidated. The homeobox gene Gax is expressed in vascular endothelial cells and inhibits proliferation and tube formation in vitro. We hypothesized that Gax is a negative transcriptional regulator of the endothelial cell angiogenic phenotype and studied its regulation and activity in vascular endothelial cells. Several proangiogenic factors caused a rapid down-regulation of Gax mRNA in human vascular endothelial cells, as did conditioned media from breast cancer cell lines. In addition, Gax expression using a replication-deficient adenoviral vector inhibited human umbilical vein endothelial cell migration toward proangiogenic factors in vitro and inhibited angiogenesis in vivo in Matrigel plugs. To identify putative downstream targets of Gax, we examined changes in global gene expression in endothelial cells due to Gax activity. Gax expression resulted in changes in global gene expression consistent with a quiescent, nonangiogenic phenotype, with increased expression of cyclin kinase inhibitors and decreased expression of genes implicated in endothelial cell activation and angiogenesis. Further analysis revealed that Gax downregulated numerous nuclear factor-k kB (NF-k kB) target genes and decreased the binding of NF-k kB to its target sequence in electrophoretic mobility shift assays. To our knowledge, Gax is the first homeobox gene described that inhibits NF-k kB activity in vascular endothelial cells. Because NF-k kB has been implicated in endothelial cell activation and angiogenesis, the down-regulation of NF-k kB-dependent genes by Gax suggests one potential mechanism by which Gax inhibits the angiogenic phenotype. (Cancer Res 2005; 65(4): 1414-24)

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“…In general, CGI differential methylation was associated with up-or down-regulation of genes implicated in angiogenesis, vascular smooth muscle cells (VSMCs) phenotype modulation and inflammation. One remarkable example was the opposite effects on HOXC and HOXD members, known to promote vascular remodelling and inhibit adult angiogenesis, respectively (22). HOXCs located in physical proximity to a DM-CGI unmethylated in AAs were selectively expressed in AAs, whereas the precisely opposite pattern was observed in HOXD10.…”

Section: Discussionmentioning

confidence: 99%

Extensive demethylation of normally hypermethylated CpG islands occurs in human atherosclerotic arteries

Castillo-Díaz

Garay-Sevilla²,

Hernández-González³

et al. 2010

Int J Mol Med

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Abstract. Global DNA hypomethylation potentially leading to pro-atherogenic gene expression occurs in atherosclerotic lesions. However, limited information is available on the genomic location of hypomethylated sequences. We present a microarray-based survey of the methylation status of CpG islands (CGIs) in 45 human atherosclerotic arteries and 16 controls. Data from 10,367 CGIs revealed that a subset (151 or 1.4%) of these was hypermethylated in control arteries. The vast majority (142 or 94%) of this CGI subset was found to be unmethylated or partially methylated in atherosclerotic tissue, while only 17 of the normally unmethylated CGIs were hypermethylated in the diseased tissue. The most common functional classes among annotated genes adjacent to or containing differentially methylated CGIs, were transcription (23%) and signalling factors (16%). The former included HOX members, PROX1, NOTCH1 and FOXP1, which are known to regulate key steps of atherogenesis. Expression analysis revealed differential expression of all CGI-associated genes analysed. Sequence analysis identified novel DNA motifs with regulatory potential, associated with differentially methylated CGIs. This study is the first large-scale analysis of DNA methylation in atherosclerosis. Our data suggest that aberrant DNA methylation in atherosclerosis affects the transcription of critical regulatory genes for the induction of a pro-atherogenic cellular phenotype.

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Control of Vascular Cell Differentiation by Homeobox Transcription Factors

Cited by 65 publications

References 60 publications

Cumulative methylation alternations of gene promoters and protein markers for diagnosis of epithelial ovarian cancer

Cumulative methylation alternations of gene promoters and protein markers for diagnosis of epithelial ovarian cancer

The Homeobox Gene Gax Inhibits Angiogenesis through Inhibition of Nuclear Factor-κB–Dependent Endothelial Cell Gene Expression

Extensive demethylation of normally hypermethylated CpG islands occurs in human atherosclerotic arteries

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