Abstract
Ephrin receptors (Ephs) are reported to control metastatic signaling of non-small cell lung cancer (NSCLC) and other tumors. Here we show for the first time that blocking expression of the Eph ligand Ephrin B3 inhibits NSCLC cell migration and invasion. We demonstrate that Ephrin B3 directly binds the EphAs EphA2, EphA3, EphA4, and EphA5. EphA2 Ser897 was previously shown to drive migration propensity of tumor cells and our study reveals that EphA2 stays phosphorylated on Ser897 in the Ephrin B3/EphA2 complex in NSCLC cells of different histology. Moreover, we report that within such Ephrin B3/EphA2 complex both Akt Ser 129 and p38MAPK are found indicating a potential to drive migration/proliferation. We also found the EMT marker E-cadherin expression to be maintained or increased upon Ephrin B3 blockade in NSCLC cells. Expression of Ephrin B3 was furthermore analyzed in a cohort of NSCLC stage IA-IB cases (n=200) alongside EphA2 and Ephrin A1. We found that Ephrin B3 was concomitantly expressed with EphA2 and Ephrin A1 with higher Ephrin B3 levels found in non-squamous than in squamous tumors, whereas EphA2 was higher expressed in well-differentiated than in low-differentiated tumors. In the entire NSCLC cohort, Ephrin B3 expression was not linked to patient survival, whereas a high EphA2 expression was associated with improved survival (p=0.03). In conclusion, we show that blocking Ephrin B3 expression inhibits NSCLC proliferation-, migration- and invasion capacity which calls for further studies on interference with Ephrin B3 as a possible therapeutic avenue in this tumor malignancy.
Highlights
Non-small cell lung cancer (NSCLC) is one of the top ranked tumor types when it comes to both incidence and cancer-associated death worldwide [1]
Our results demonstrate that inhibition of Ephrin B3 decrease nonsmall cell lung cancer (NSCLC) cell proliferation, migration and invasion and in line with previous reports corroborate a role of EphA2 blockade in the same signaling events
Tyrosine kinase signaling via EphA upon Ephrin A ligand binding activates and represses multiple cellular pathways in normal cells whereas in tumors these pathways are often altered e.g. by different Ephrin ligand expression or Ephrin receptors (Ephs) binding pattern or by Eph kinase mutations resulting in increased proliferation, migrationand invasion capacity [3]
Summary
Non-small cell lung cancer (NSCLC) is one of the top ranked tumor types when it comes to both incidence and cancer-associated death worldwide [1]. Binding of the cell bound Ephrin ligands, which can be of A or B subtype, to the ligand binding domain of the Eph receptor, which may be of A or B subtype, results in phosphorylation of tyrosine residues in the Eph kinase domain. This leads to subsequent signaling alteration in downstream kinase networks e.g. MAPKs, PI3K/Akt and Src, a signaling www.impactjournals.com/oncotarget event called “forward signaling” (reviewed in [3]). Recent findings points towards a role of EphA2 in driving resistance towards inhibitors of mutated EGFR illustrating the importance of EphA2 in NSCLC malignancy in response to clinically applied targeted therapy [31]
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