Regulation of transcription factor E2F3a and its clinical relevance in ovarian cancer

Abstract

Recently we showed an integral epidermal growth factor receptor (EGFR)-E2F3a signaling path, in which E2F3a was found to be essential in EGFR-mediated proliferation in ovarian cancer cells. The present work evaluates the clinical relevance of this novel axis and of E2F3a itself in a large set of 130 ovarian cancer specimens. For this purpose E2F3a and its counterpart, E2F3b, were measured by RT-PCR and activated EGFR was assessed by immunohistochemistry. When compared with healthy control tissue, both E2F3 isoforms were overexpressed in the cancers, but only E2F3a expression correlated with tumor stage (q ¼ 0.349, P ¼ 0.0001) and residual disease (q ¼ 0.254, P ¼ 0.004). Univariate survival analyses showed E2F3a and activated EGFR to be associated with poor PFS and OS. Furthermore, a strong, positive correlation between activated EGFR and E2F3a expression was shown (P ¼ 0.0001). We further identified two EGFR-independent mechanisms that regulate E2F3a expression, namely one, acting by promoter methylation of miR-34a, which by its physical interaction with E2F3a transcripts causes their degradation, and the second based on 6p22 gene locus amplification. MiRIDIAN-based knockdown and induction of miR-34a evidenced a direct regulatory link between miR-34a and E2F3a, and the tumor-suppressive character of miR-34a was documented by its association with improved survival. Although, 6p22 gene locus amplification was detected in a significant number of ovarian cancer specimens, 6p22 ploidy was not relevant in predicting survival. In Cox regression analysis, E2F3a, but not activated EGFR or miR-34a expression, retained independent prognostic significance (PFS: hazards ratio 3.785 (1.326-9.840), P ¼ 0.013; OS: hazards ratio 4.651 (1.189-15.572), P ¼ 0.013). These clinical findings highlight the relevance of E2F3a in the biology of ovarian cancer. Moreover, identification of EGFR-independent mechanisms in E2F3a control can be helpful in explaining the non-responsiveness of therapeutic EGFR targeting in ovarian cancer.

Dysregulation of MicroRNA-34a Expression in Head and Neck Squamous Cell Carcinoma Promotes Tumor Growth and Tumor Angiogenesis

“…Recently, Chen et al, demonstrated that out of two different E2F3 isoforms, E2F3a showed significantly higher oncogenic potential as compared to E2F3b [54]. Similarly, Reimer et al, have shown that although both E2F3 isoforms were overexpressed in tumor samples, but only E2F3a expression directly correlated with tumor stage and residual disease in ovarian cancer patients [55]. In addition, the same group has also shown that there was a strong correlation between E2F3a expression and activated EGFR in ovarian cancer specimens and that E2F3a was a key player in EGFR driven cell proliferation [56].…”

Comprehensive analysis of long non-coding RNA expression profiles in hepatitis B virus-related hepatocellular carcinoma

“…E2F3 is a member of the E2F transcription factors that are master regulators of many biological processes, like DNA repair, apoptosis, cell cycle, and centrosome duplication [29]. E2F3 is overexpressed in various cancers and drives tumorigenesis [30]. RAF1 is also a pro-oncogene and serves as a part of the mitogen-activated protein kinases/extracellular signal-regulated kinase signal transduction pathway and regulates cell migration, apoptosis, and differentiation.…”

Role of miR-34a as a suppressor of L1CAM in endometrial carcinoma

“…MiR-34a is known as a tumor suppressor miRNA and is a transcriptional target of p53 [21]. MiR-34a was shown to play an important role in the regulation of EMT [22] and can target a variety of genes involved in tumor progression such as c-Met [23], SNAIL [24], E2F3a [25], PDGFR-aß [26]. Most recently, reduced chemoresistance and migration, as well as regulation of sternness markers in colorectal cancer cells were associated with miR-34a mediated repression of c-Kit by p53.…”