title: Ephrin B3 interacts with multiple EphA receptors and drives migration and invasion in non-small cell lung cancer.
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.
authors.affiliation: Karolinska Biomics Center, Department of Oncology-Pathology, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
authors.forename: Ghazal
authors.initials: G
authors.lastname: Efazat
authors.affiliation: Karolinska Biomics Center, Department of Oncology-Pathology, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
authors.forename: Metka
authors.initials: M
authors.lastname: Novak
authors.affiliation: Institute of Environmental Medicine, Division of Toxicology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors.forename: Vitaliy O
authors.initials: VO
authors.lastname: Kaminskyy
authors.affiliation: Karolinska Biomics Center, Department of Oncology-Pathology, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
authors.forename: Luigi
authors.initials: L
authors.lastname: De Petris
authors.affiliation: Karolinska Biomics Center, Department of Oncology-Pathology, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
authors.forename: Lena
authors.initials: L
authors.lastname: Kanter
authors.affiliation: Karolinska Biomics Center, Department of Oncology-Pathology, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
authors.forename: Therese
authors.initials: T
authors.lastname: Juntti
authors.affiliation: Department of Molecular Medicine and Surgery (MMK), Thoracic Surgery, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Bergman
authors.affiliation: Institute of Environmental Medicine, Division of Toxicology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors.forename: Boris
authors.initials: B
authors.lastname: Zhivotovsky
authors.affiliation: Karolinska Biomics Center, Department of Oncology-Pathology, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
authors.forename: Rolf
authors.initials: R
authors.lastname: Lewensohn
authors.affiliation: Karolinska Biomics Center, Department of Oncology-Pathology, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
authors.forename: Petra
authors.initials: P
authors.lastname: Hååg
authors.affiliation: Karolinska Biomics Center, Department of Oncology-Pathology, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
authors.forename: Kristina
authors.initials: K
authors.lastname: Viktorsson
mesh_terms: D000072283:A549 Cells; D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics; D036382:Ephrin-A1 / Q000235:genetics / Q000378:metabolism; D036389:Ephrin-B3 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D011485:Protein Binding; D034622:RNA Interference; D036104:Receptor, EphA2 / Q000235:genetics / Q000378:metabolism; D036081:Receptors, Eph Family / Q000235:genetics* / Q000378:metabolism
chemical_list: D036382:Ephrin-A1; D036389:Ephrin-B3; D036104:Receptor, EphA2; D036081:Receptors, Eph Family
keywords: EphA2; Ephrin B3; NSCLC; invasion; migration