The tumour-promoting receptor tyrosine kinase, EphB4, regulates expression of Integrin-[beta]8 in prostate cancer cells

Background The EphB4 receptor tyrosine kinase is overexpressed in many cancers including prostate cancer. The molecular mechanisms by which this ephrin receptor influences cancer progression are complex as there are tumor-promoting ligand-independent mechanisms in place as well as ligand-dependent t...

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Bibliographic Details
Published in:BMC cancer 2015-03, Vol.15
Main Authors: Mertens-Walker, Inga, Fernandini, Bruno C, Maharaj, Mohanan SN, Rockstroh, Anja, Nelson, Colleen C, Herington, Adrian C, Stephenson, Sally-Anne
Format: Article
Language:English
Subjects:
Analysis
Cancer cells
DNA microarrays
Genes
Genetic aspects
Instrument industry
Prostate cancer
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Summary:Background The EphB4 receptor tyrosine kinase is overexpressed in many cancers including prostate cancer. The molecular mechanisms by which this ephrin receptor influences cancer progression are complex as there are tumor-promoting ligand-independent mechanisms in place as well as ligand-dependent tumor suppressive pathways. Methods We employed transient knockdown of EPHB4 in prostate cancer cells, coupled with gene microarray analysis, to identify genes that were regulated by EPHB4 and may represent linked tumor-promoting factors. We validated target genes using qRT-PCR and employed functional assays to determine their role in prostate cancer migration and invasion. Results We discovered that over 500 genes were deregulated upon EPHB4 siRNA knockdown, with integrin [beta]8 (ITGB8) being the top hit (29-fold down-regulated compared to negative non-silencing siRNA). Gene ontology analysis found that the process of cell adhesion was highly deregulated and two other integrin genes, ITGA3 and ITGA10, were also differentially expressed. In parallel, we also discovered that over-expression of EPHB4 led to a concomitant increase in ITGB8 expression. In silico analysis of a prostate cancer progression microarray publically available in the Oncomine database showed that both EPHB4 and ITGB8 are highly expressed in prostatic intraepithelial neoplasia, the precursor to prostate cancer. Knockdown of ITGB8 in PC-3 and 22Rv1 prostate cancer cells in vitro resulted in significant reduction of cell migration and invasion. Conclusions These results reveal that EphB4 regulates integrin [beta]8 expression and that integrin [beta]8 plays a hitherto unrecognized role in the motility of prostate cancer cells and thus targeting integrin [beta]8 may be a new treatment strategy for prostate cancer. Keywords: EphB4, Prostate cancer, Integrin-[beta]8
ISSN:1471-2407
1471-2407
DOI:10.1186/s12885-015-1164-6