EFNA3 long noncoding RNAs induced by hypoxia promote metastatic dissemination

L. Gómez-Maldonado; M. Tiana; O. Roche; A. Prado-Cabrero; L. Jensen; A. Fernandez-Barral; I. Guijarro-Muñoz; E. Favaro; G. Moreno-Bueno; L. Sanz; J. Aragones; A. Harris; O. Volpert; B. Jimenez; L. Del Peso

doi:10.1038/onc.2014.200

EFNA3 long noncoding RNAs induced by hypoxia promote metastatic dissemination

L. Gómez-Maldonado, M. Tiana, O. Roche, A. Prado-Cabrero, L. Jensen, A. Fernandez-Barral, I. Guijarro-Muñoz, E. Favaro, G. Moreno-Bueno, L. Sanz, J. Aragones, A. Harris, O. Volpert, B. Jimenez, L. Del Peso^*

^*Corresponding author for this work

Urology

Research output: Contribution to journal › Article › peer-review

91 Scopus citations

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.

Original language	English (US)
Pages (from-to)	2609-2620
Number of pages	12
Journal	Oncogene
Volume	34
Issue number	20
DOIs	https://doi.org/10.1038/onc.2014.200
State	Published - May 14 2015

Funding

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).

ASJC Scopus subject areas

Molecular Biology
Genetics
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/onc.2014.200

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Gómez-Maldonado, L., Tiana, M., Roche, O., Prado-Cabrero, A., Jensen, L., Fernandez-Barral, A., Guijarro-Muñoz, I., Favaro, E., Moreno-Bueno, G., Sanz, L., Aragones, J., Harris, A., Volpert, O., Jimenez, B., & Del Peso, L. (2015). EFNA3 long noncoding RNAs induced by hypoxia promote metastatic dissemination. Oncogene, 34(20), 2609-2620. https://doi.org/10.1038/onc.2014.200

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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.",

author = "L. G{\'o}mez-Maldonado and M. Tiana and O. Roche and A. Prado-Cabrero and L. Jensen and A. Fernandez-Barral and I. Guijarro-Mu{\~n}oz and E. Favaro and G. Moreno-Bueno and L. Sanz and J. Aragones and A. Harris and O. Volpert and B. Jimenez and {Del Peso}, L.",

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Gómez-Maldonado, L, Tiana, M, Roche, O, Prado-Cabrero, A, Jensen, L, Fernandez-Barral, A, Guijarro-Muñoz, I, Favaro, E, Moreno-Bueno, G, Sanz, L, Aragones, J, Harris, A, Volpert, O, Jimenez, B & Del Peso, L 2015, 'EFNA3 long noncoding RNAs induced by hypoxia promote metastatic dissemination', Oncogene, vol. 34, no. 20, pp. 2609-2620. https://doi.org/10.1038/onc.2014.200

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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.

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.

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ER -

EFNA3 long noncoding RNAs induced by hypoxia promote metastatic dissemination

Abstract

Funding

ASJC Scopus subject areas

UN SDGs

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