E2F transcription factors and digestive system malignancies: How much do we know?

Abstract

E2F family of transcription factors regulates various cellular functions related to cell cycle and apoptosis. Its individual members have traditionally been classified into activators and repressors, based on in vitro studies. However their contribution in human cancer is more complicated and difficult to predict. We review current knowledge on the expression of E2Fs in digestive system malignancies and its clinical implications for patient prognosis and treatment. E2F1, the most extensively studied member and the only one with prognostic value, exhibits a tumor-suppressing activity in esophageal, gastric and colorectal adenocarcinoma, and in hepatocellular carcinoma (HCC), whereas in pancreatic ductal adenocarcinoma and esophageal squamous cell carcinoma may function as a tumor-promoter. In the latter malignancies, E2F1 immunohistochemical expression has been correlated with higher tumor grade and worse patient survival, whereas in esophageal, gastric and colorectal adenocarcinomas is a marker of increased patient survival. E2F2 has only been studied in colorectal cancer, where its role is not considered significant. E2F4's role in colorectal, gastric and hepatic carcinogenesis is tumor-promoting. E2F8 is strongly upregulated in human HCC, thus possibly contributing to hepatocarcinogenesis. Adenoviral transfer of E2F as gene therapy to sensitize pancreatic cancer cells for chemotherapeutic agents has been used in experimental studies. Other therapeutic strategies are yet to be developed, but it appears that targeted approaches using E2F-agonists or antagonists should take into account the tissue-dependent function of each E2F member. Further understanding of E2Fs' contribution in cellular functions in vivo would help clarify their role in carcinogenesis.

Competitive Binding Between Id1 and E2F1 to Cdc20 Regulates E2F1 Degradation and Thymidylate Synthase Expression to Promote Esophageal Cancer Chemoresistance

“…including esophageal cancer (34), but amplification of E2F1 in cancer is rare. As in the case for many transcription factors, E2F1 is mainly regulated by posttranslational modification.…”

MicroRNA-125a Regulates Cell Proliferation Via Directly Targeting E2F2 in Osteosarcoma

“…It plays an important role in cell proliferation and cell cycle regulation [27]. E2F2 is a member of the E2F transcription factor family, which functions as a proto-oncogenes, and its increased expression can promote the proliferation of tumor cells.…”

The Spectrum of E2F in Liver Disease-Mediated Regulation in Biology and Cancer

“…E2Fs are at the crossroads of cell cycle regulation and key players in current cancer research. The typical E2Fs contain a DNA‐binding domain (DBD) that is evolutionarily preserved and associate with a dimerization partner (DPs) protein to form a heterodimer complex, which binds promoters of target genes (Rowland and Bernards, ; Sun et al, ; Xanthoulis and Tiniakos, ). This classic paradigm of dimerization is true for typical E2Fs ( E2f1–E2f6 ).…”

“…The CDK‐RB‐E2F pathway is functionally inactivated in most cases of HCC by genetic, epigenetic, and/or viral mechanisms (Viatour et al, ). Although it seems easy to conclude that overexpression of the E2F activators would be proto‐oncogenic and overexpression of the repressors would be tumor‐suppressive, this is an oversimplification and inaccurate (Rowland and Bernards, ; Tsai et al, ; Lammens et al, ; Chen et al, , ; Jiang et al, ; Xanthoulis and Tiniakos et al, ). RB is functionally inactivated in the majority of HCCs either by direct mutation or loss of the RB protein through altered CDK activity and therefore the role of E2F and RB in HCC must be understood.…”

“…E2F1 has been shown in liver and other tissues at different times to be proto‐oncogenic by inducing cell proliferation and tumor suppressing by promoting apoptosis (DeGregori et al, ; Deng et al, ; Palaiologou et al, ; Xanthoulis and Tiniakos, ). Multiple reports have been published linking overexpression of E2F1 or E2F3 to hepatocellular carcinoma as well as bladder, retinoblastoma, liposarcoma, glioblastoma, lung, ovarian, breast, gastric, and other malignancies in humans (Midorikawa et al, ; Chen et al, ; Wang et al, ,b; Chen et al, ; Xanthoulis and Tiniakos, ; Zeng et al, ). A c‐myc induced mouse model for hepatocarcinogenesis demonstrated nicely using immunohistochemistry (IHC) increased E2F1 and E2F2 as well as free E2F1‐ and E2F2‐DP1 (although E2F2 was more variable) expression in tumor tissue, proliferating liver, and apoptotic liver and virtually absent in non‐tumor tissue (Santoni‐Rugiu et al, ).…”