title: ETV5 transcription program links BDNF and promotion of EMT at invasive front of endometrial carcinomas.
abstract: Myometrial infiltration represents a main clinical determinant of endometrial carcinomas (EC) presenting as aggressive high-grade deeply invasive neoplasms, substantially associated with risk of recurrence and death. The up-regulation of ETV5 transcription factor linked to the promotion of epithelial to mesenchymal transition is considered as a basic mechanism underlying the initial steps of EC invasion. In this work, we aimed to investigate the transcription program of tumor invasion regulated by ETV5. We performed a comparative Chip-on-chip analysis at invasive front and superficial area of human EC. ETV5 specific binding to promoter regions of genes related to cellular migration, adhesion and invasion at deep invasion tumor areas highlighted the relevance of neural networks associated with cellular plasticity. Interestingly, brain-derived neurotrophic factor (BDNF) demonstrated a principal role orchestrating ETV5-mediated epithelial-to-mesenchymal transition in endometrial cancer. Impairment of the BDNF/tropomyosin-related kinase B (TrkB)/extracellular signal-regulated kinase axis in endometrial cancer cell lines reversed the aggressive and invasive phenotype promoted by the up-regulation of ETV5 at the invasive front of EC. Likewise, BDNF directly impacted on the efficiency of ETV5 promoted metastasis in a mice model of endometrial distant dissemination. These results translate the recognized role of BDNF/TrkB on neural plasticity into a relevant cancer metastasis event; suggest common mechanisms shared by neural development and tumor invasion; and offer new therapeutic opportunities specifically directed against disseminated disease in endometrial cancer.
authors.affiliation: Translational Medical Oncology, Health Research Institute of Santiago (IDIS), Fundacion Ramon Dominguez, SERGAS, Trav. Choupana s/n, 15706 Santiago de Compostela, Spain, Oncology Pathology Group, Dept. de Ciencies Mediques Basiques, Universitat de Lleida, Hospital Universitari Arnau de Vilanova, Institut de Recerca Biomedica de Lleida, IRBLleida, 25198 Lleida, Spain, Liquid Biopsy Analysis Unit, Health Research Institute of Santiago (IDIS), Complexo Hospitalario Universitario de Santiago de Compostela (SERGAS), Trav. Choupana s/n, 15706 Santiago de Compostela, Spain and Research Unit in Biomedicine, Vall d'Hebron Research Institute and Hospital and Universitat Autonoma de Barcelona, 08035 Barcelona, Spain.
authors.forename: Lorena
authors.initials: L
authors.lastname: Alonso-Alconada
authors.affiliation: Oncology Pathology Group, Dept. de Ciencies Mediques Basiques, Universitat de Lleida, Hospital Universitari Arnau de Vilanova, Institut de Recerca Biomedica de Lleida, IRBLleida, 25198 Lleida, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Eritja
authors.affiliation: Liquid Biopsy Analysis Unit, Health Research Institute of Santiago (IDIS), Complexo Hospitalario Universitario de Santiago de Compostela (SERGAS), Trav. Choupana s/n, 15706 Santiago de Compostela, Spain and.
authors.forename: Laura
authors.initials: L
authors.lastname: Muinelo-Romay
authors.affiliation: Translational Medical Oncology, Health Research Institute of Santiago (IDIS), Fundacion Ramon Dominguez, SERGAS, Trav. Choupana s/n, 15706 Santiago de Compostela, Spain, Oncology Pathology Group, Dept. de Ciencies Mediques Basiques, Universitat de Lleida, Hospital Universitari Arnau de Vilanova, Institut de Recerca Biomedica de Lleida, IRBLleida, 25198 Lleida, Spain, Liquid Biopsy Analysis Unit, Health Research Institute of Santiago (IDIS), Complexo Hospitalario Universitario de Santiago de Compostela (SERGAS), Trav. Choupana s/n, 15706 Santiago de Compostela, Spain and Research Unit in Biomedicine, Vall d'Hebron Research Institute and Hospital and Universitat Autonoma de Barcelona, 08035 Barcelona, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Barbazan
authors.affiliation: Translational Medical Oncology, Health Research Institute of Santiago (IDIS), Fundacion Ramon Dominguez, SERGAS, Trav. Choupana s/n, 15706 Santiago de Compostela, Spain, Oncology Pathology Group, Dept. de Ciencies Mediques Basiques, Universitat de Lleida, Hospital Universitari Arnau de Vilanova, Institut de Recerca Biomedica de Lleida, IRBLleida, 25198 Lleida, Spain, Liquid Biopsy Analysis Unit, Health Research Institute of Santiago (IDIS), Complexo Hospitalario Universitario de Santiago de Compostela (SERGAS), Trav. Choupana s/n, 15706 Santiago de Compostela, Spain and Research Unit in Biomedicine, Vall d'Hebron Research Institute and Hospital and Universitat Autonoma de Barcelona, 08035 Barcelona, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Lopez-Lopez
authors.affiliation: Oncology Pathology Group, Dept. de Ciencies Mediques Basiques, Universitat de Lleida, Hospital Universitari Arnau de Vilanova, Institut de Recerca Biomedica de Lleida, IRBLleida, 25198 Lleida, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Matias-Guiu
authors.affiliation: Research Unit in Biomedicine, Vall d'Hebron Research Institute and Hospital and Universitat Autonoma de Barcelona, 08035 Barcelona, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Gil-Moreno
authors.affiliation: Oncology Pathology Group, Dept. de Ciencies Mediques Basiques, Universitat de Lleida, Hospital Universitari Arnau de Vilanova, Institut de Recerca Biomedica de Lleida, IRBLleida, 25198 Lleida, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Dolcet
authors.affiliation: Translational Medical Oncology, Health Research Institute of Santiago (IDIS), Fundacion Ramon Dominguez, SERGAS, Trav. Choupana s/n, 15706 Santiago de Compostela, Spain, Oncology Pathology Group, Dept. de Ciencies Mediques Basiques, Universitat de Lleida, Hospital Universitari Arnau de Vilanova, Institut de Recerca Biomedica de Lleida, IRBLleida, 25198 Lleida, Spain, Liquid Biopsy Analysis Unit, Health Research Institute of Santiago (IDIS), Complexo Hospitalario Universitario de Santiago de Compostela (SERGAS), Trav. Choupana s/n, 15706 Santiago de Compostela, Spain and Research Unit in Biomedicine, Vall d'Hebron Research Institute and Hospital and Universitat Autonoma de Barcelona, 08035 Barcelona, Spain miguel.abal.posada@sergas.es.
authors.forename: Miguel
authors.initials: M
authors.lastname: Abal
mesh_terms: D000818:Animals; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D004268:DNA-Binding Proteins; C086680:ETV5 protein, human; D012333:RNA, Messenger; D014157:Transcription Factors; C579455:BDNF protein, human