Etv5 Transcription Factor Is Upregulated In Ovarian Cancer And Contributes To Ovarian Tumor Progression And Dissemination

ETV5 transcription factor is upregulated in ovarian cancer and contributes to ovarian tumor progression and dissemination
Marta Llauradó 1, Bsc, Miguel Abal1, PhD, Josep Castellví2, MD, Eva Colás1, Bsc, Sílvia Cabrera 1,3, MD, Antonio Gil-Moreno3,5, MD, PhD, Asumpció Pérez-Benavente3, MD, Andreas Doll1, PhD, Xavier Dolcet4, PhD , Xavier Matias-Guiu4, PhD, MD, Mónica Vázquez-Levin, PhD 6 ,JaumeReventós1,5 , PhD, MD and Anna Ruiz1, PhD.
1Biomedical Research Unit, Research Institute Vall d’Hebron University Hospital, Barcelona, Spain; 2Pathology Department, Vall d'Hebron University Hospital; 3Gynecological Oncology Department, Vall d'Hebron University Hospital; 4Oncologic Pathology Group, Institut de Recerca Biomèdica de Lleida, IRBLleida, Lleida, Spain, 5Faculty of Medicine, AutonomaUniversity of Barcelona, Barcelona, Spain. 6Instituto de Biología y Medicina, CONICET, Buenos Aires, Argentina.
Short title: ETV5 role in ovarian cancer
Corresponding author:
Dr Jaume Reventós and Dr Anna Ruiz
Biomedical Research Unit,
Institut de Recerca Hospital Vall d’Hebron,
Passeig Vall d'Hebron, 119-129, 08035 Barcelona, Spain
Phone: +34-93-4894067
Fax: +34-93-4894015
e-mail:annruiz@ir.vhebron.net; jreventos@ir.vhebron.net




Abstract
Epithelial ovarian cancer is the most lethal gynecological malignancy and the fifth leading cause of cancer deaths in women in the Western world. ETS transcription factors are known to act as positive or negative regulators of the expression of genes that are involved in various biological processes, including those that controlcellular proliferation, differentiation, apoptosis, tissue remodeling, angiogenesis and transformation. ETV5 belongs to the PEA3 subfamily. PEA3 subfamily members are able to activate the transcription of proteases, MMPs and TIMPs, which is central to both tumor invasion and angiogenesis. Here, we examined the role of the ETV5 transcription factor in epithelial ovarian cancer and we found ETV5upregulated in ovarian tumor samples compared to ovarian tissue controls. The in vitro inhibition of ETV5 decreased cell proliferation in serum-deprived conditions, induced EMT and decreased cell adhesion to extracellular matrix components. ETV5 inhibition also decreased cell-cell adhesion and induced apoptosis in anchorage independent conditions. Accordingly, ETV5 upregulation induced the expressionof cell adhesion molecules and enhanced cell survival in an spheroid model. Our findings suggest that the overexpression of ETV5 detected in ovarian cancer cells may contribute to ovarian tumor progression through the ability of ETV5 to enhance ovarian cancer cell proliferation. In addition, ETV5 upregulation would play a role in ovarian cancer cell dissemination and metastasis into theperitoneal cavity by protecting ovarian cancer cells from apoptosis and by increasing the adhesion of ovarian cancer cells to the peritoneal wall through the regulation of cell adhesion molecules.
Keywords: ETV5, ETS transcription factors, ovarian cancer, tumor invasion and tumor dissemination



Introduction
Epithelial ovarian cancer is the most lethal gynecological malignancy and the fifth leadingcause of cancer deaths in women in the Western world (Jemal et al., 2007). Largely asymptomatic, over 70% of the patients are already at an advanced stage at initial diagnosis. The five year survival rate for women with advanced stage disease is less than 20%. In contrast, the cure rate is almost 90% when women are diagnosed at an early stage (Aletti et al., 2007).
The ETS family oftranscription factors play a role in several physiological and pathological processes such as embryogenesis, wound healing and tumor progression (Sementchenko and Watson, 2000). ETS transcription factors have been implicated in the regulation of gene expression during a variety of biological processes including cell growth and differentiation (Sharrocks, 2001). In particular, ETS transcription factors are...