Carcinogenesis Advance Access originally published online on May 14, 2009
Carcinogenesis 2009 30(8):1288-1297; doi:10.1093/carcin/bgp119
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Proteomic approach to ETV5 during endometrial carcinoma invasion reveals a link to oxidative stress
Biomedical Research Unit, Research Institute, Vall d'Hebron University Hospital
1 Department of Gynecological Oncology
2 Department of Pathology, Vall d'Hebron University Hospital, Barcelona 08035, Spain
3 Department of Medical Oncology, Complexo Hospitalario Universitario, Santiago de Compostela 15706, Spain
4 Department of Obstetrics and Gynecology, Hospital del Mar
5 Department of Pathology, Hospital del Mar, Barcelona 08003, Spain
6 Proteomics Laboratory, Medical Oncology Research Programme, Research Institute, Vall d'Hebron University Hospital, Barcelona 08035, Spain
7 Department of Experimental Pathology and Medical Biotechnology, University of Pisa, Pisa I-56127, Italy
* To whom correspondence should be addressed. Translational Oncology Laboratory, Instituto de Investigación Sanitaria de Santiago, Complexo Hospitalario Universitario Santiago de Compostela, Travesia. Choupana s/n, Santiago de Compostela 15706, Spain. Tel: +34 981955073; Fax: +34 981951081; Email: miguel.abal.posada{at}sergas.es
Endometrial cancer, the most common gynecological malignancy in western countries, is characterized by a favorable prognosis. Nonetheless, deep myometrial invasion correlates with more undifferentiated tumors, lymph-vascular invasion, node involvement and decreased global survival. We have described previously the Ets family member ERM/ETV5 specifically upregulated in endometrial endometrioid carcinoma (EEC) associated with myometrial infiltration. To understand the role of this transcription factor during myometrial infiltration, we analyzed by two-dimension differential gel electrophoresis (2D-DIGE) technology those proteins whose expression was altered in endometrial cell lines stably overexpressing ERM/ETV5. Pathway analysis pointed to actin regulation and transforming growth factor beta and progesterone signaling as processes regulated by ERM/ETV5. In addition, we characterized the specific upregulation of the nuclear dehydrogenase/reductase Hep27 as well as its ERM/ETV5-dependent mitochondrial localization. Further functional studies demonstrated a protective role of Hep 27 against apoptosis induced by oxidative stress. Overall, the ETV5-related proteomic approach performed in the Hec-1A cell line reinforces a role of this transcription factor in the regulation of the migratory and invasive tumor behavior and points to a modulated response to oxidative stress associated with the promotion of invasion in endometrial cancer. Unraveling the molecular events in EEC associated with the initiation of tumor invasion would represent an obvious improvement in the pursuit of rational targets for the onset of metastasis. This knowledge would also be a valuable tool for the molecular stratification of patients since myometrial affectation determines an increase in the rate of recurrence after a first surgical treatment and a decrease in 5 year survival.
Abbreviations: 2D-DIGE, two-dimension differential gel electrophoresis; DHE, dihydroethidium; EEC, endometrial endometrioid carcinoma; GFP, green fluorescent protein; mAb, monoclonal antibody; MALDI, matrix-assisted laser desorption; MS, ionization-mass spectrometry; PBS, phosphate-buffered saline; rAb, rabbit polyclonal antibody; ROS, reactive oxygen species; SDR, short-chain dehydrogenases/reductase; SDS, sodium dodecyl sulfate; siRNA, small interfering RNA; TOF, time of flight; TGFβ, transforming growth factor beta
These authors are the Principal Investigators of this work. Received November 19, 2008; revised April 9, 2009; accepted May 8, 2009.