Oncotarget

Research Papers:

E2F3 upregulation promotes tumor malignancy through the transcriptional activation of HIF-2α in clear cell renal cell carcinoma

Yu Gao, Hongzhao Li, Xin Ma, Yang Fan, Dong Ni, Yu Zhang, Qingbo Huang, Kan Liu, Xintao Li, Lei Wang, Yuanxin Yao, Qing Ai and Xu Zhang _

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Oncotarget. 2017; 8:54021-54036. https://doi.org/10.18632/oncotarget.10568

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Abstract

Yu Gao1,2,*, Hongzhao Li1,2,*, Xin Ma1,2,*, Yang Fan1,2, Dong Ni1,2, Yu Zhang1,2, Qingbo Huang1,2, Kan Liu1,2, Xintao Li1,2, Lei Wang1,2, Yuanxin Yao1,2, Qing Ai1,2 and Xu Zhang1,2

1Department of Urology, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, 100853, P. R. China

2State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital/Chinese PLA Medical School, Beijing, 100853, P. R. China

*These authors have contributed equally to this work

Correspondence to:

Xu Zhang, email: [email protected]

Keywords: clear cell renal cell carcinoma, E2F3, hypoxia-inducible factor-2, transcriptional regulation, carcinogenesis

Received: December 29, 2015     Accepted: May 20, 2016     Published: July 13, 2016

ABSTRACT

The E2F3 transcriptional regulatory pathway plays a major part in multiple-cancer progression, but the specific contributions of this pathway to tumor formation and the progression of clear cell renal cell carcinoma (ccRCC) are not fully understood. Clinically, we demonstrated that E2F3 was overexpressed in advanced tumor features. Moreover, cytoplasmic restoration predicted the poor overall survival of ccRCC patients. As a remarkable oncogene for ccRCC, high HIF-2α levels closely correlated with E2F3 upregulation. We observed in vitro that E2F3 overexpression and knockdown regulated HIF-2α expression. Furthermore, we found that HIF-2α harbored multiple E2F3 binding sites in the promoters. Mechanistically, E2F3 acted to transactivate HIF-2α transcription, which in turn exerted a serial effect on the pivotal epithelial–mesenchymal transition-related genes. The RNA interference-mediated silencing of HIF-2α attenuated E2F3-enhanced cell migration and invasion in vitro and in vivo. Overall, our results identified HIF-2α as a direct target gene for E2F3 upregulation, which was critical for carcinogenesis and progression of ccRCC. Thus, targeting the E2F3–HIF-2α interaction may be a promising approach to ccRCC treatment.


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