Overexpression of E2F1 Promotes Tumor Malignancy And Correlates with TNM Stages in Clear Cell Renal Cell Carcinoma

Abstract

BackgroundTranscription factor E2F1 exerts effects on many types of cancers. As an upstream regulator of a host of genes, E2F1 can trigger diverse aberrant transcription processes that may dominate malignancy. Clear cell renal cell carcinoma (ccRCC) is the most common subtype in renal cell carcinoma which displays high malignancy and has a shortage of biomarkers in clinics. Our study aimed to explore the function of E2F1 in ccRCC and its correlation with clinicopathological parameters.Methodology/Principle FindingsTranscription factor E2F1 was mainly distributed in cancer cell nucleus and mRNA expression significantly increased in 72 cases of clear cell renal cell carcinoma (ccRCC) tissues compared with adjacent non-cancerous kidney tissues (p<0.001). The protein expression was consistent with mRNA expression. Further analysis in 92 cases indicated that E2F1 mRNA level expression was associated with the tumor pathologic parameters embracing diameter, Fuhrman tumor grade, pT stage, TNM stage grouping and macrovascular infiltration (MAVI). These surgical specimens had high grade tumors accompanied with an elevated E2F1 expression. Moreover, E2F1 transfection was found to contribute significantly to cancer cell proliferation, migration and invasion in vitro.Conclusions/SignificanceOverexpression of E2F1 may be a key event in the local and vascular infiltration of ccRCC indicated by the activation of matrix metalloproteinase (MMP) 2 and MMP9. These findings highlighted the implication of E2F1’s function in the metastatic process. Furthermore, the clinical relevance of E2F1 in ccRCC pointed to a potential new therapeutic target.

A Murine Model of K-RAS and β-Catenin Induced Renal Tumors Expresses High Levels of E2F1 and Resembles Human Wilms Tumor

“…In adult clear cell renal cell carcinoma (ccRCC), E2F1 has been shown to be elevated in several studies 23, 24 , which is consistent with the results presented here. This is likely due, at least in part, to the observation that the protein product of the VHL gene (pVHL) inhibits E2F1 expression 23 .…”

“…In addition, E2F’s have been shown to be elevated in adult renal malignancies 23, 24 . We therefore interrogated other members of the E2F gene family and found E2F1 is part of the concordant gene signature shared by human WT’s and murine Kras G12D /Catnb Δex3 tumor bearing kidneys.…”

KLF6 Suppresses Metastasis of Clear Cell Renal Cell Carcinoma via Transcriptional Repression of E2F1

“…Certain studies reported that E2F1 disrupts a range of pathways in numerous cancers and is closely correlated with clinical parameters (13)(14)(15). We had also previously identified that E2F1 is upregulated in ccRCC progression (16).…”

Differential impact of RB status on E2F1 reprogramming in human cancer

“…Few pathways were attenuated after RB depletion, despite the total number of genes altered in this category, underscoring the focused nature of E2F1 activity to elicit specific transcriptional programs. Pathways with attenuated enrichment include those that have been previously shown to interplay with the RB/E2F1 axis, such as epithelial-mesenchymal transition, hedgehog signaling, and myogenesis (Figure 6C, left; normalized enrichment score < -1.3) (59)(60)(61)(62)(63)(64). Conversely, a number of clinically relevant pathways were enriched upon RB loss, including canonical E2F targets, Myc targets, mitotic spindle, and DNA repair (Figure 6C, right; normalized enrichment score > 1.3).…”