Proteomic approach to ETV5 during endometrial carcinoma invasion reveals a link to oxidative stress.
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.
Monge
Marta
M
Biomedical Research Unit, Research Institute, Vall d'Hebron University Hospital, Barcelona 08035, Spain.
Colas
Eva
E
Doll
Andreas
A
Gil-Moreno
Antonio
A
Castellvi
Josep
J
Diaz
Berta
B
Gonzalez
Marta
M
Lopez-Lopez
Rafael
R
Xercavins
Jordi
J
Carreras
Ramon
R
Alameda
Francesc
F
Canals
Francesc
F
Gabrielli
Franco
F
Reventos
Jaume
J
Abal
Miguel
M
D000426:Alcohol Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000429:Alcohol Oxidoreductases; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D000074409:Carbonyl Reductase (NADPH); D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015180:Electrophoresis, Gel, Two-Dimensional; D016889:Endometrial Neoplasms / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D011374:Progesterone / Q000378:metabolism; D040901:Proteomics; D034741:RNA, Small Interfering / Q000494:pharmacology; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013347:Subcellular Fractions; D014157:Transcription Factors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C086680:ETV5 protein, human; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D011374:Progesterone; D000429:Alcohol Oxidoreductases; D000426:Alcohol Dehydrogenase; D000074409:Carbonyl Reductase (NADPH); C095961:DHRS2 protein, human