Review
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World J Gastroenterol. Jun 7, 2013; 19(21): 3189-3198
Published online Jun 7, 2013. doi: 10.3748/wjg.v19.i21.3189
E2F transcription factors and digestive system malignancies: How much do we know?
Athanasios Xanthoulis, Dina G Tiniakos
Athanasios Xanthoulis, Department of Surgery, Section of Gastroenterological Surgery, Levanger Hospital, Nord-Trøndelag Hospital Trust, 7600 Levanger, Norway
Dina G Tiniakos, Laboratory of Histology-Embryology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
Author contributions: Xanthoulis A contributed to the literature search, manuscript writing and final revision of the article; Tiniakos DG contributed to the study idea, study design and final revision of the article; both authors have approved the final version of the manuscript.
Supported by “Kapodistrias” Research Program, Special Accounts Research Fund 70/4/6549, National and Kapodistrian University of Athens, Greece
Correspondence to: Dina G Tiniakos, MD, PhD, Laboratory of Histology-Embryology, Medical School, National and Kapodistrian University of Athens, 75 M Asias street, 11527 Athens, Greece. dtiniak@med.uoa.gr
Telephone: +30-210-7462362 Fax: +30-210-7462340
Received: December 12, 2012
Revised: March 20, 2013
Accepted: March 28, 2013
Published online: June 7, 2013
Processing time: 174 Days and 5.1 Hours
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.

Keywords: E2F; Colorectal cancer; Gastric cancer; Esophageal cancer; Pancreatic cancer; Hepatocellular carcinoma; Digestive system malignancies

Core tip: The E2F family of transcription factors has been in the focus of cancer research because its members regulate significant cellular functions related to cell cycle and apoptosis. E2Fs may act either as tumor-promoters or as tumor-suppressors, depending on the tissue. This review highlights the role of E2Fs in digestive system malignancies and their possible implication in diagnosis, treatment and prognosis.