Regulation of Ephrin-A3 expression by hypoxia through a novel IncRNA-mediated mechanism: a potential role in cancer metastasis

• Autores: Laura Gómez Maldonado
• Directores de la Tesis: Luis del Peso Ovalle (dir. tes.)
• Lectura: En la Universidad Autónoma de Madrid ( España ) en 2013
• Idioma: inglés
• Tribunal Calificador de la Tesis: Alberto Muñoz Terol (presid.), José Manuel González Sancho (secret.), José Arturo Calzada García (voc.), Ricardo Sánchez Prieto (voc.), Diego Villar Lozano (voc.)
• Materias:
  • Ciencias médicas
    • Patología
      • Oncología
• Enlaces
  • Tesis en acceso abierto en: Biblos-e Archivo
• Resumen

  • Regulation of Ephrin-A3 expression by hypoxia through a novel IncRNA-mediated mechanism. A potential role in cancer metastasis" Tumor hypoxia strongly correlates with metastasis and poor survival. However, the molecular mechanism by which hypoxia drives metastasis formation is not clear yet. EFNA3, a member of the ephrin type A ligands, was identified as a potential novel HIF target gene in an in silico search performed by our group (Ortiz-Barahona, Villar, Pescador, Amigo, & Del Peso, 2010). Although the involvement of EFNA3 in cancer has not been studied in detail, the expression of other ephrin members and their receptors are increased in human tumors and correlate with increased metastatic potential. Here, we show that hypoxia regulates Ephrin-A3 expression through a non-direct mechanism that involves the HIF-mediated transcriptional induction of a novel family of long-noncoding RNAs (lncRNAs) from the EFNA3 locus. In turn, these lncRNAs favor Ephrin-A3 accumulation acting at the postranscriptional level. As a consequence of this mechanism, EFNA3 transcript expression is significantly augmented in human renal carcinoma, where HIF is constitutively active, as compared with normal kidney tissue. Importantly, we found a strong correlation between high EFNA3 expression and shorter metastasis-free survival in breast cancer patients, suggesting a role for Ephrin-A3 in the promotion of metastatic behavior. In support of this hypothesis, Ephrin-A3 expression increased the metastatic potential of human breast cancer cells in an orthotopic xenotransplantation model. Importantly, by a combination of in vitro an in vivo experiments, we also found that Ephrin-A3 expression increases the ability of tumor cells to extravasate from the blood vessels into surrounding tissue. This function is in agreement with the role of ephrins as key mediators intercellular adhesion-repulsion and suggest a mechanisms for the promotion of metastasis. Altogether, our results suggest that hypoxia contributes to metastatic spread of cancer cells via HIF-mediated induction of EFNA3 lncRNAs and subsequent protein accumulation.