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.
Highlights
Renal cell carcinoma (RCC), whose most common subtype is clears cell, is a urologic malignant neoplasm that may be fatal [1]
We evaluated the correlation between E2F3 expression levels and the clinicopathological features of clear cell renal cell carcinoma (ccRCC) patients in subcellular localization (Table 1)
Mammalian E2F3 is a well-characterized transcription factor functioning in a cell cycle-dependent manner with specific binding to pRB, linking cell cycle proteins, such as cyclin-dependent kinases (CDKs) and cyclins [18]
Summary
Renal cell carcinoma (RCC), whose most common subtype is clears cell, is a urologic malignant neoplasm that may be fatal [1]. Few clinical measures are effective for late stage clear cell renal cell carcinoma (ccRCC), and the most widely one is biological targeted therapy [2]. The outcome of patients with high clinical stage and metastatic RCC (mRCC) is inevitably poor [3]. The molecular mechanism underlying the pathogenesis of ccRCC needs to be explored. E2F3 and other E2F transcription factors are the prevalent regulators of various genes. Dissociated with Rb protein, E2Fs1-3 exert their functions in the way of transcriptional activation [5]. The full mode of action of E2F3 in ccRCC has not yet been characterized
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