title: EFNA3 long noncoding RNAs induced by hypoxia promote metastatic dissemination.
abstract: The presence of hypoxic regions in solid tumors is an adverse prognostic factor for patient outcome. Here, we show that hypoxia induces the expression of Ephrin-A3 through a novel hypoxia-inducible factor (HIF)-mediated mechanism. In response to hypoxia, the coding EFNA3 mRNA levels remained relatively stable, but HIFs drove the expression of previously unknown long noncoding (lnc) RNAs from EFNA3 locus and these lncRNA caused Ephrin-A3 protein accumulation. Ephrins are cell surface proteins that regulate diverse biological processes by modulating cellular adhesion and repulsion. Mounting evidence implicates deregulated ephrin function in multiple aspects of tumor biology. We demonstrate that sustained expression of both Ephrin-A3 and novel EFNA3 lncRNAs increased the metastatic potential of human breast cancer cells, possibly by increasing the ability of tumor cells to extravasate from the blood vessels into surrounding tissue. In agreement, we found a strong correlation between high EFNA3 expression and shorter metastasis-free survival in breast cancer patients. Taken together, our results suggest that hypoxia could contribute to metastatic spread of breast cancer via HIF-mediated induction of EFNA3 lncRNAs and subsequent Ephrin-A3 protein accumulation.
authors.affiliation: Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM) and Instituto de Investigaciones Biomédicas 'Alberto Sols' (CSIC-UAM), Madrid, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Gómez-Maldonado
authors.affiliation: Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM) and Instituto de Investigaciones Biomédicas 'Alberto Sols' (CSIC-UAM), Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Tiana
authors.affiliation: 1] Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM) and Instituto de Investigaciones Biomédicas 'Alberto Sols' (CSIC-UAM), Madrid, Spain [2] IdiPaz, Instituto de Investigación Sanitaria del Hospital Universitario La Paz, Madrid, Spain.
authors.forename: O
authors.initials: O
authors.lastname: Roche
authors.affiliation: Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM) and Instituto de Investigaciones Biomédicas 'Alberto Sols' (CSIC-UAM), Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Prado-Cabrero
authors.affiliation: 1] Department of Medicine and Health Sciences, Linköping University Linköping, Sweden [2] Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Jensen
authors.affiliation: Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM) and Instituto de Investigaciones Biomédicas 'Alberto Sols' (CSIC-UAM), Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Fernandez-Barral
authors.affiliation: Molecular Immunology Unit, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Guijarro-Muñoz
authors.affiliation: Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
authors.forename: E
authors.initials: E
authors.lastname: Favaro
authors.affiliation: Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM) and Instituto de Investigaciones Biomédicas 'Alberto Sols' (CSIC-UAM), Madrid, Spain.
authors.forename: G
authors.initials: G
authors.lastname: Moreno-Bueno
authors.affiliation: Molecular Immunology Unit, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Sanz
authors.affiliation: Research Unit, Hospital Universitario Santa Cristina, Research Institute Princesa, Autonomous University of Madrid, Madrid, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Aragones
authors.affiliation: Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
authors.forename: A
authors.initials: A
authors.lastname: Harris
authors.affiliation: Urology Department, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: O
authors.initials: O
authors.lastname: Volpert
authors.affiliation: Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM) and Instituto de Investigaciones Biomédicas 'Alberto Sols' (CSIC-UAM), Madrid, Spain.
authors.forename: B
authors.initials: B
authors.lastname: Jimenez
authors.affiliation: 1] Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM) and Instituto de Investigaciones Biomédicas 'Alberto Sols' (CSIC-UAM), Madrid, Spain [2] IdiPaz, Instituto de Investigación Sanitaria del Hospital Universitario La Paz, Madrid, Spain.
authors.forename: L
authors.identifier: 0000000340145688
authors.initials: L
authors.lastname: del Peso
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D036384:Ephrin-A3 / Q000235:genetics / Q000378:metabolism; D005260:Female; D056426:Genetic Loci; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D062085:RNA, Long Noncoding / Q000096:biosynthesis* / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis* / Q000235:genetics; D015027:Zebrafish
chemical_list: D036384:Ephrin-A3; D051793:Hypoxia-Inducible Factor 1; D009363:Neoplasm Proteins; D062085:RNA, Long Noncoding; D012334:RNA, Neoplasm