Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Regulation of Angiogenesis by EZH2

ABSTRACT: While VEGF-targeted therapies are showing promise in clinical studies, new angiogenesis targets are needed to make additional gains. Here, we show that increased Zeste homologue 2 (EZH2) expression in either tumor cells or in tumor vasculature is predictive of poor clinical outcome. The increase in endothelial EZH2 is a direct result of VEGF stimulation and indicates the presence of a paracrine circuit that promotes angiogenesis by methylating and silencing vasohibin 1 (VASH1). EZH2 silencing in the tumor-associated endothelial cells resulted in inhibition of angiogenesis mediated by reactivation of VASH1, and reduced ovarian cancer growth. Combined, these data provide a new understanding of the regulation of tumor angiogenesis and support the potential for targeting EZH2 as a novel therapeutic approach. Pre-clinical study, DNA microarray (Illumina HumanHT-12)

ORGANISM(S): Homo sapiens

SUBMITTER: Adnan Munkarah

PROVIDER: E-GEOD-20381 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Regulation of tumor angiogenesis by EZH2.

Lu Chunhua C Han Hee Dong HD Mangala Lingegowda S LS Ali-Fehmi Rouba R Newton Christopher S CS Ozbun Laurent L Armaiz-Pena Guillermo N GN Hu Wei W Stone Rebecca L RL Munkarah Adnan A Ravoori Murali K MK Shahzad Mian M K MM Lee Jeong-Won JW Mora Edna E Langley Robert R RR Carroll Amy R AR Matsuo Koji K Spannuth Whitney A WA Schmandt Rosemarie R Jennings Nicholas B NB Goodman Blake W BW Jaffe Robert B RB Nick Alpa M AM Kim Hye Sun HS Guven Eylem Ozturk EO Chen Ya-Huey YH Li Long-Yuan LY Hsu Ming-Chuan MC Coleman Robert L RL Calin George A GA Denkbas Emir B EB Lim Jae Yun JY Lee Ju-Seog JS Kundra Vikas V Birrer Michael J MJ Hung Mien-Chie MC Lopez-Berestein Gabriel G Sood Anil K AK

Cancer cell 20100801 2

Although VEGF-targeted therapies are showing promise, new angiogenesis targets are needed to make additional gains. Here, we show that increased Zeste homolog 2 (EZH2) expression in either tumor cells or in tumor vasculature is predictive of poor clinical outcome. The increase in endothelial EZH2 is a direct result of VEGF stimulation by a paracrine circuit that promotes angiogenesis by methylating and silencing vasohibin1 (vash1). Ezh2 silencing in the tumor-associated endothelial cells inhibit ...[more]

PMID: 20708159

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Project description:Abstract: Background & Aims: Unusual hypervascularity is a hallmark of human hepatocellular carcinoma (HCC). Although microRNA-214 (miR-214) is upregulated in other human cancers, it is downregulated in HCC. We elucidated the biological and clinical significance of miR-214 downregulation in HCC. Methods: MicroRNAs deregulated in HCC were identified using array-based MicroRNA profiling. A luciferase reporter assay confirmed target association between miR-214 and hepatoma-derived growth factor (HDGF). Tube formation and in vivo angiogenesis assays validated the roles of miR-214/HDGF in angiogenesis. Results: MiR-214 downregulation was associated with higher tumor recurrence and worse clinical outcomes. Ectopic expression of miR-214 suppressed xenograft tumor growth and microvascularity of the tumor and its surrounding tissues. The genes downregulated by ectopic expression of miR-214 were involved in the regulation of apoptosis, cell cycle, and angiogenesis. Integrated analysis disclosed HDGF as a downstream target of miR-214. Conditioned medium of HCC cells contained bioactivity to stimulate tube formation of human umbilical vein endothelial cells, which was abolished by pretreatment of the conditioned media with HDGF antibodies, silencing of HDGF expression or ectopic expression of miR-214 in the donor HCC cells. The angiogenic activity of the conditioned media lost by ectopic expression of miR-214 in the donor cells was restored by supplementation with recombinant HDGF. In vivo tumor angiogenesis assays showed significant suppression of tumor vascularity by ectopic expression of miR-214. Conclusions: A novel role of microRNA in tumrigenesis is identified. Downregulation of miR-214 contributes to unusual hypervascularity of HCC via activation of the HDGF paracrine pathway for tumor angiogenesis. To identify miRNAs that are deregulated in human HCC, 68 HCC and 21 non-tumor liver tissues were subjected to profiling of miRNA expression using miRNA arrays containing 739 human miRNA probes. Differentially expressed microRNAs were identified.

Dataset Information

Regulation of Angiogenesis by EZH2

Publications

Regulation of tumor angiogenesis by EZH2.

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