Critical role for the receptor tyrosine kinase EPHB4 in esophageal cancers

Rifat Hasina, Nathan Mollberg, Ichiro Kawada, Karun Mutreja, Geetanjali Kanade, Soheil Yala, Mosmi Surati, Ren Liu, Xiuqing Li, Yue Zhou, Benjamin D. Ferguson, Vidya Nallasura, Kenneth S. Cohen, Elizabeth Hyjek, Jeffery Mueller, Rajani Kanteti, Essam El Hashani, Dorothy Kane, Yutaka Shimada, Mark W. LingenAliya N. Husain, Mitchell C. Posner, Irving Waxman, Victoria M. Villaflor, Mark K. Ferguson, Lyuba Varticovski, Everett E. Vokes, Parkash Gill, Ravi Salgia

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Esophageal cancer incidence is increasing and has few treatment options. In studying receptor tyrosine kinases associated with esophageal cancers, we have identi fi ed EPHB4 to be robustly overexpressed in cell lines and primary tumor tissues. In total, 94 squamous cell carcinoma, 82 adenocarcinoma, 25 dysplasia, 13 Barrett esophagus, and 25 adjacent or unrelated normal esophageal tissues were evaluated by immunohistochemistry. EPHB4 expression was signi ficantly higher in all the different histologic categories than in adjacent normal tissues. In 13 esophageal cancer cell lines, 3 of the 9 SCC cell lines and 2 of the 4 adenocarcinomas expressed very high levels of EPHB4. An increased gene copy number ranging from 4 to 20 copies was identified in a subset of the overexpressing patient samples and cell lines. We have developed a novel 4-nitroquinoline 1-oxide (4-NQO)-induced mouse model of esophageal cancer that recapitulates the EPHB4 expression in humans. A specific small-molecule inhibitor of EPHB4 decreased cell viability in a timeand dose-dependent manner in 3 of the 4 cell lines tested. The small-molecule inhibitor and an EPHB4 siRNA also decreased cell migration (12%- 40% closure in treated vs. 60%-80% in untreated), with decreased phosphorylation of various tyrosyl-containing proteins, EphB4, and its downstream target p125FAK. Finally, in a xenograft tumor model, an EPHB4 inhibitor abrogated tumor growth by approximately 60% compared with untreated control. EphB4 is robustly expressed and potentially serves as a novel biomarker for targeted therapy in esophageal cancers.

Original languageEnglish
Pages (from-to)184-194
Number of pages11
JournalCancer Research
Volume73
Issue number1
DOIs
Publication statusPublished - 2013 Jan 1
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Hasina, R., Mollberg, N., Kawada, I., Mutreja, K., Kanade, G., Yala, S., Surati, M., Liu, R., Li, X., Zhou, Y., Ferguson, B. D., Nallasura, V., Cohen, K. S., Hyjek, E., Mueller, J., Kanteti, R., El Hashani, E., Kane, D., Shimada, Y., ... Salgia, R. (2013). Critical role for the receptor tyrosine kinase EPHB4 in esophageal cancers. Cancer Research, 73(1), 184-194. https://doi.org/10.1158/0008-5472.CAN-12-0915