Oncotarget

Research Papers:

EZH2 promotes angiogenesis through inhibition of miR-1/Endothelin-1 axis in nasopharyngeal carcinoma

Juan Lu, Fei-Peng Zhao, Zengliu Peng, Meng-Wen Zhang, Shao-Xiong Lin, Bi-Jun Liang, Bao Zhang, Xiong Liu, Lu Wang, Gang Li, Wen-Dong Tian, Ying Peng, Ming-Liang He and Xiang-Ping Li _

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Oncotarget. 2014; 5:11319-11332. https://doi.org/10.18632/oncotarget.2435

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Abstract

Juan Lu1,*, Fei-Peng Zhao1,*, Zengliu Peng2,*, Meng-Wen Zhang1, Shao-Xiong Lin1,3, Bi-Jun Liang1, Bao Zhang4, Xiong Liu1, Lu Wang1, Gang Li1, Wen-Dong Tian1, Ying Peng5,6, Ming-Liang He7 and Xiang-Ping Li1

1 Department of Otolaryngology-Head and Neck Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China

2 Lab of Otolaryngology & Head and Neck tumor, Nanfang Hospital, Southern Medical University, Guangzhou, China

3 Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital, Shantou University Medical College, Shantou, China

4 School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, China

5 Department of Neurology, The Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

6 Key Laboratory of malignant tumor gene regulation and target therapy of Guangdong Higher Education Institutes, Sun Yat-sen University, Guangzhou, China

7 Department of Biomedical Science, City University of Hong Kong, Hong Kong, China

* These authors contributed equally to this work

Correspondence:

Xiang-Ping Li, email:

Ming-Liang He, email:

Keywords: EZH2; miR-1; Endothelin-1; angiogenesis; nasopharyngeal carcinoma

Received: July 19, 2014 Accepted: September 02, 2014 Published: September 03, 2014

Abstract

Emerging evidence clearly indicates that EZH2 plays a crucial role in tumor angiogenesis. However, the role of EZH2 in angiogenesis is still unknown in nasopharyngeal carcinoma (NPC). We here showed that the elevated EZH2 level was closely associated with an aggressive and poor prognostic phenotype, and was positively correlated with microvessel density (MVD) in NPC tissues. Functional studies showed that EZH2 upregulation promoted cell proliferation, migration and tubule formation of endothelial cells, and knockdown of EZH2 suppressed tumor growth, metastasis and angiogenesis in vivo. Mechanistic investigations revealed that EZH2 inhibited miR-1 transcription via promoter binding activity, leading to enhanced expression of Endothelin-1 (ET-1) which is suppressed by miR-1 targeting of ET-1 3’UTR. Furthermore, knockdown of EZH2 or overexpression of miR-1 exerted anti-angiogenic effect on NPC cells. More importantly, the neutralizing antibody against ET-1 significantly abrogated the pro-angiogenic effect of EZH2, and forced expression of ET-1 rescued the anti-angiogenic effect induced by EZH2 knockdown. In clinical specimens, ET-1 was widely overexpressed and associated with clinical stage and MVD. Taken together, our results identify a novel signaling pathway involved in NPC angiogenesis, and also suggest that EZH2-miR-1-ET-1 axis represents multiple potential therapeutic targets for NPC.


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