Global Evaluation of Eph Receptors and Ephrins in Lung Adenocarcinomas Identifies EphA4 As an Inhibitor of Cell Migration and Invasion

Overview

Journal Mol Cancer Ther

Date 2012 Jul 19

PMID 22807579

Citations 36

Authors

Pierre Saintigny

Shaohua Peng

Li Zhang

Banibrata Sen

Ignacio I Wistuba

Scott M Lippman

Luc Girard

John D Minna

John V Heymach

Faye M Johnson

Affiliations

Soon will be listed here.

Abstract

The Eph family of receptors is the largest family of receptor tyrosine kinases, but it remains poorly studied in lung cancer. We aimed to systematically explore the human Eph receptors and their ligands, the ephrins, in lung adenocarcinoma. The prognostic impact of Eph receptor and ephrin gene expression was analyzed using 2 independent cohorts of lung adenocarcinoma. Gene expression profiles in lung adenocarcinoma compared with normal adjacent lung were studied in 3 independent cohorts and in cell lines. Gene expression profiles were validated with quantitative polymerase chain reaction (qPCR) and Western blotting in cell lines. Functional studies to assess the role of Eph receptor A4 (EphA4) were carried out in vitro. The biological effects of EphA4 in lung cancer cell lines were assayed following overexpression and knockdown. Of the 11 Eph receptors and 8 ephrins analyzed, only EphA4 and ephrin A1 gene expression were consistently associated with an improved outcome in patients with lung adenocarcinoma. Expression levels of EphA4 by microarray correlated well with expression levels measured by qPCR and Western blotting. EphA4 overexpression reduced cell migration and invasion but did not affect cell cycle, apoptosis, or drug sensitivity. Surprisingly, EphA4 was expressed at higher levels in cancer compared with non-cancer tissues and cell lines. EphA4 gene expression is associated with an improved outcome in patients with resected lung adenocarcinoma, possibly by affecting cancer cell migration and invasion.

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References

Zhou B, Peyton M, He B, Liu C, Girard L, Caudler E . Targeting ADAM-mediated ligand cleavage to inhibit HER3 and EGFR pathways in non-small cell lung cancer. Cancer Cell. 2006; 10(1):39-50. PMC: 4451119. DOI: 10.1016/j.ccr.2006.05.024. View

van Doorn R, Dijkman R, Vermeer M, Out-Luiting J, van der Raaij-Helmer E, Willemze R . Aberrant expression of the tyrosine kinase receptor EphA4 and the transcription factor twist in Sézary syndrome identified by gene expression analysis. Cancer Res. 2004; 64(16):5578-86. DOI: 10.1158/0008-5472.CAN-04-1253. View

Oshima T, Akaike M, Yoshihara K, Shiozawa M, Yamamoto N, Sato T . Overexpression of EphA4 gene and reduced expression of EphB2 gene correlates with liver metastasis in colorectal cancer. Int J Oncol. 2008; 33(3):573-7. View

Ji X, Li G, Feng Y, Zhao J, Li J, Sun Z . EphB3 is overexpressed in non-small-cell lung cancer and promotes tumor metastasis by enhancing cell survival and migration. Cancer Res. 2011; 71(3):1156-66. DOI: 10.1158/0008-5472.CAN-10-0717. View

Gentleman R, Carey V, Bates D, Bolstad B, Dettling M, Dudoit S . Bioconductor: open software development for computational biology and bioinformatics. Genome Biol. 2004; 5(10):R80. PMC: 545600. DOI: 10.1186/gb-2004-5-10-r80. View

Sen B, Peng S, Saigal B, Williams M, Johnson F . Distinct interactions between c-Src and c-Met in mediating resistance to c-Src inhibition in head and neck cancer. Clin Cancer Res. 2010; 17(3):514-24. PMC: 3460647. DOI: 10.1158/1078-0432.CCR-10-1617. View

Bisson N, Poitras L, Mikryukov A, Tremblay M, Moss T . EphA4 signaling regulates blastomere adhesion in the Xenopus embryo by recruiting Pak1 to suppress Cdc42 function. Mol Biol Cell. 2007; 18(3):1030-43. PMC: 1805096. DOI: 10.1091/mbc.e06-04-0294. View

Qin H, Shi J, Noberini R, Pasquale E, Song J . Crystal structure and NMR binding reveal that two small molecule antagonists target the high affinity ephrin-binding channel of the EphA4 receptor. J Biol Chem. 2008; 283(43):29473-84. PMC: 2662028. DOI: 10.1074/jbc.M804114200. View

Davies H, Hunter C, Smith R, Stephens P, Greenman C, Bignell G . Somatic mutations of the protein kinase gene family in human lung cancer. Cancer Res. 2005; 65(17):7591-5. DOI: 10.1158/0008-5472.CAN-05-1855. View

10.

Ramalingam S, Owonikoko T, Khuri F . Lung cancer: New biological insights and recent therapeutic advances. CA Cancer J Clin. 2011; 61(2):91-112. DOI: 10.3322/caac.20102. View

11.

Sayers E, Barrett T, Benson D, Bolton E, Bryant S, Canese K . Database resources of the National Center for Biotechnology Information. Nucleic Acids Res. 2011; 40(Database issue):D13-25. PMC: 3245031. DOI: 10.1093/nar/gkr1184. View

12.

Park E, Warner N, Bong Y, Stapleton D, Maeda R, Pawson T . Ectopic EphA4 receptor induces posterior protrusions via FGF signaling in Xenopus embryos. Mol Biol Cell. 2004; 15(4):1647-55. PMC: 379263. DOI: 10.1091/mbc.e03-09-0674. View

13.

Bhattacharjee A, Richards W, Staunton J, Li C, Monti S, Vasa P . Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses. Proc Natl Acad Sci U S A. 2001; 98(24):13790-5. PMC: 61120. DOI: 10.1073/pnas.191502998. View

14.

Lockwood W, Chari R, Coe B, Girard L, MacAulay C, Lam S . DNA amplification is a ubiquitous mechanism of oncogene activation in lung and other cancers. Oncogene. 2008; 27(33):4615-24. PMC: 2849646. DOI: 10.1038/onc.2008.98. View

15.

Barrios A, Poole R, Durbin L, Brennan C, Holder N, Wilson S . Eph/Ephrin signaling regulates the mesenchymal-to-epithelial transition of the paraxial mesoderm during somite morphogenesis. Curr Biol. 2003; 13(18):1571-82. DOI: 10.1016/j.cub.2003.08.030. View

16.

Noberini R, Koolpe M, Peddibhotla S, Dahl R, Su Y, Cosford N . Small molecules can selectively inhibit ephrin binding to the EphA4 and EphA2 receptors. J Biol Chem. 2008; 283(43):29461-72. PMC: 2570887. DOI: 10.1074/jbc.M804103200. View

17.

Shedden K, Taylor J, Enkemann S, Tsao M, Yeatman T, Gerald W . Gene expression-based survival prediction in lung adenocarcinoma: a multi-site, blinded validation study. Nat Med. 2008; 14(8):822-7. PMC: 2667337. DOI: 10.1038/nm.1790. View

18.

Iiizumi M, Hosokawa M, Takehara A, Chung S, Nakamura T, Katagiri T . EphA4 receptor, overexpressed in pancreatic ductal adenocarcinoma, promotes cancer cell growth. Cancer Sci. 2006; 97(11):1211-6. PMC: 11158844. DOI: 10.1111/j.1349-7006.2006.00313.x. View

19.

Ashida S, Nakagawa H, Katagiri T, Furihata M, Iiizumi M, Anazawa Y . Molecular features of the transition from prostatic intraepithelial neoplasia (PIN) to prostate cancer: genome-wide gene-expression profiles of prostate cancers and PINs. Cancer Res. 2004; 64(17):5963-72. DOI: 10.1158/0008-5472.CAN-04-0020. View

20.

Stahl S, Branca R, Efazat G, Ruzzene M, Zhivotovsky B, Lewensohn R . Phosphoproteomic profiling of NSCLC cells reveals that ephrin B3 regulates pro-survival signaling through Akt1-mediated phosphorylation of the EphA2 receptor. J Proteome Res. 2011; 10(5):2566-78. DOI: 10.1021/pr200037u. View