TY - JOUR
T1 - EFNA3 long noncoding RNAs induced by hypoxia promote metastatic dissemination
AU - Gómez-Maldonado, L.
AU - Tiana, M.
AU - Roche, O.
AU - Prado-Cabrero, A.
AU - Jensen, L.
AU - Fernandez-Barral, A.
AU - Guijarro-Muñoz, I.
AU - Favaro, E.
AU - Moreno-Bueno, G.
AU - Sanz, L.
AU - Aragones, J.
AU - Harris, A.
AU - Volpert, O.
AU - Jimenez, B.
AU - Del Peso, L.
N1 - Funding Information:
We thank Amparo Acker-Palmer for expert advice on ephrin detection and Ignacio Palmero DGCR8 reagents. This work was supported by Ministerio de Ciencia e Innovación (Spanish Ministry of Science and Innovation, MICINN) (grant numbers SAF2008-03147 and SAF2011_24225 to LdelP and SAF-2010-19256 to BJ); by Comunidad Autónoma de Madrid (grant numbers S2010/BMD-2542 to LdelP), by the 7th Research Framework Programme of the European Union (grant number METOXIA project ref. HEALTH-F2-2009-222741 to LdelP); by CSIC (JAE DOC 2010/FSE2007-2013 to OR) and by Fondo de Investigación Sanitaria/Instituto de Salud Carlos III (grants PI08/90856 and PS09/00227 to LS).
Publisher Copyright:
© 2015 Macmillan Publishers Limited All rights reserved.
PY - 2015/5/14
Y1 - 2015/5/14
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84938068832&partnerID=8YFLogxK
U2 - 10.1038/onc.2014.200
DO - 10.1038/onc.2014.200
M3 - Article
C2 - 25023702
AN - SCOPUS:84938068832
VL - 34
SP - 2609
EP - 2620
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 20
ER -
