Aggressive and recurrent ovarian cancers upregulate ephrinA5, a non-canonical effector of EphA2 signaling duality

Abstract Erythropoietin producing hepatocellular (Eph) receptors and their membrane-bound ligands ephrins are variably expressed in epithelial cancers, with context-dependent implications to both tumor-promoting and -suppressive processes in ways that remain incompletely understood. Using ovarian ca...

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Autores principales:	Joonas Jukonen, Lidia Moyano-Galceran, Katrin Höpfner, Elina A. Pietilä, Laura Lehtinen, Kaisa Huhtinen, Erika Gucciardo, Johanna Hynninen, Sakari Hietanen, Seija Grénman, Päivi M. Ojala, Olli Carpén, Kaisa Lehti
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ecaf312fb199488291cd2a4acc2a122b
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spelling	oai:doaj.org-article:ecaf312fb199488291cd2a4acc2a122b2021-12-02T18:27:47ZAggressive and recurrent ovarian cancers upregulate ephrinA5, a non-canonical effector of EphA2 signaling duality10.1038/s41598-021-88382-62045-2322https://doaj.org/article/ecaf312fb199488291cd2a4acc2a122b2021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-88382-6https://doaj.org/toc/2045-2322Abstract Erythropoietin producing hepatocellular (Eph) receptors and their membrane-bound ligands ephrins are variably expressed in epithelial cancers, with context-dependent implications to both tumor-promoting and -suppressive processes in ways that remain incompletely understood. Using ovarian cancer tissue microarrays and longitudinally collected patient cells, we show here that ephrinA5/EFNA5 is specifically overexpressed in the most aggressive high-grade serous carcinoma (HGSC) subtype, and increased in the HGSC cells upon disease progression. Among all the eight ephrin genes, high EFNA5 expression was most strongly associated with poor overall survival in HGSC patients from multiple independent datasets. In contrast, high EFNA3 predicted improved overall and progression-free survival in The Cancer Genome Atlas HGSC dataset, as expected for a canonical inducer of tumor-suppressive Eph receptor tyrosine kinase signaling. While depletion of either EFNA5 or the more extensively studied, canonically acting EFNA1 in HGSC cells increased the oncogenic EphA2-S897 phosphorylation, EFNA5 depletion left unaltered, or even increased the ligand-dependent EphA2-Y588 phosphorylation. Moreover, treatment with recombinant ephrinA5 led to limited EphA2 tyrosine phosphorylation, internalization and degradation compared to ephrinA1. Altogether, our results suggest a unique function for ephrinA5 in Eph-ephrin signaling and highlight the clinical potential of ephrinA5 as a cell surface biomarker in the most aggressive HGSCs.Joonas JukonenLidia Moyano-GalceranKatrin HöpfnerElina A. PietiläLaura LehtinenKaisa HuhtinenErika GucciardoJohanna HynninenSakari HietanenSeija GrénmanPäivi M. OjalaOlli CarpénKaisa LehtiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Joonas Jukonen Lidia Moyano-Galceran Katrin Höpfner Elina A. Pietilä Laura Lehtinen Kaisa Huhtinen Erika Gucciardo Johanna Hynninen Sakari Hietanen Seija Grénman Päivi M. Ojala Olli Carpén Kaisa Lehti Aggressive and recurrent ovarian cancers upregulate ephrinA5, a non-canonical effector of EphA2 signaling duality
description	Abstract Erythropoietin producing hepatocellular (Eph) receptors and their membrane-bound ligands ephrins are variably expressed in epithelial cancers, with context-dependent implications to both tumor-promoting and -suppressive processes in ways that remain incompletely understood. Using ovarian cancer tissue microarrays and longitudinally collected patient cells, we show here that ephrinA5/EFNA5 is specifically overexpressed in the most aggressive high-grade serous carcinoma (HGSC) subtype, and increased in the HGSC cells upon disease progression. Among all the eight ephrin genes, high EFNA5 expression was most strongly associated with poor overall survival in HGSC patients from multiple independent datasets. In contrast, high EFNA3 predicted improved overall and progression-free survival in The Cancer Genome Atlas HGSC dataset, as expected for a canonical inducer of tumor-suppressive Eph receptor tyrosine kinase signaling. While depletion of either EFNA5 or the more extensively studied, canonically acting EFNA1 in HGSC cells increased the oncogenic EphA2-S897 phosphorylation, EFNA5 depletion left unaltered, or even increased the ligand-dependent EphA2-Y588 phosphorylation. Moreover, treatment with recombinant ephrinA5 led to limited EphA2 tyrosine phosphorylation, internalization and degradation compared to ephrinA1. Altogether, our results suggest a unique function for ephrinA5 in Eph-ephrin signaling and highlight the clinical potential of ephrinA5 as a cell surface biomarker in the most aggressive HGSCs.
format	article
author	Joonas Jukonen Lidia Moyano-Galceran Katrin Höpfner Elina A. Pietilä Laura Lehtinen Kaisa Huhtinen Erika Gucciardo Johanna Hynninen Sakari Hietanen Seija Grénman Päivi M. Ojala Olli Carpén Kaisa Lehti
author_facet	Joonas Jukonen Lidia Moyano-Galceran Katrin Höpfner Elina A. Pietilä Laura Lehtinen Kaisa Huhtinen Erika Gucciardo Johanna Hynninen Sakari Hietanen Seija Grénman Päivi M. Ojala Olli Carpén Kaisa Lehti
author_sort	Joonas Jukonen
title	Aggressive and recurrent ovarian cancers upregulate ephrinA5, a non-canonical effector of EphA2 signaling duality
title_short	Aggressive and recurrent ovarian cancers upregulate ephrinA5, a non-canonical effector of EphA2 signaling duality
title_full	Aggressive and recurrent ovarian cancers upregulate ephrinA5, a non-canonical effector of EphA2 signaling duality
title_fullStr	Aggressive and recurrent ovarian cancers upregulate ephrinA5, a non-canonical effector of EphA2 signaling duality
title_full_unstemmed	Aggressive and recurrent ovarian cancers upregulate ephrinA5, a non-canonical effector of EphA2 signaling duality
title_sort	aggressive and recurrent ovarian cancers upregulate ephrina5, a non-canonical effector of epha2 signaling duality
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/ecaf312fb199488291cd2a4acc2a122b
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Aggressive and recurrent ovarian cancers upregulate ephrinA5, a non-canonical effector of EphA2 signaling duality

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