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.
Highlights
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
High EFNA5 was associated to poor 5-year overall survival (OS) (Fig. 1A; Supplementary Fig. 1B; p = 0.001). This association remained significant with extended survival time analysis (13-year; Fig. 1B; Supplementary Fig. 1C; p = 0.010) as well as when k-means clustering was used for patient grouping (Supplementary Fig. 1B; p = 0.003), and high EFNA5 showed a trend to shorter time to recurrence/progression-free survival (PFS) (Fig. 1C)
The tumor-suppressive signaling elicited by EphA2-ephrinA complexes is often halted in aggressive cancers via EphA2 receptor overexpression coupled with ephrinA ligand d ownregulation[12]
Summary
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. 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. In distinct OC datasets, this context-dependent signaling has been linked to different clinical outcomes based on, for instance, association of high EPHA2 and EPHA4 expression with poor patient s urvival[16,17,18,19,20,21,22,23,24,25,26] Among their ligands, opposing clinical associations have instead been reported for EFNA1 and EFNA516,18. Upon interaction with ephrinA ligand, EphA2 transphosphorylation at specific cytoplasmic tyrosine residues leads to the receptor activation, followed by internalization of the receptor-ligand complex and eventually receptor degradation or dephosphorylation[12,28] This signaling mode has been mostly related to the anti-invasive and growth-suppressive cancer cell functions. In addition to targeting Eph receptors, altering the signaling elicited by the ephrin ligands can help to revert the tumor-promoting signaling to a suppressive s tate[33,34]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
