Abstract
BackgroundThe 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.MethodsWe 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.ResultsWe discovered that over 500 genes were deregulated upon EPHB4 siRNA knockdown, with integrin β8 (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.ConclusionsThese results reveal that EphB4 regulates integrin β8 expression and that integrin β8 plays a hitherto unrecognized role in the motility of prostate cancer cells and thus targeting integrin β8 may be a new treatment strategy for prostate cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1164-6) contains supplementary material, which is available to authorized users.
Highlights
The EphB4 receptor tyrosine kinase is overexpressed in many cancers including prostate cancer
Erythropoietin-producing hepatocellular (Eph) Type-B receptor 4 (EphB4) is part of the largest family of membrane-bound receptor tyrosine kinases (RTK) which consists of 14 different receptors which are classed as EphA or EphB
EPHB4 down-regulation results in differential gene expression in LNCaP cells In an effort to characterize the contribution of EphB4 to regulating gene expression in prostate cancer, endogenously EphB4-expressing LNCaP cells were transfected with EPHB4 specific siRNAs and compared to negative non-silencing siRNA cells using gene expression profiling
Summary
The EphB4 receptor tyrosine kinase is overexpressed in many cancers including prostate cancer. Erythropoietin-producing hepatocellular (Eph) Type-B receptor 4 (EphB4) is part of the largest family of membrane-bound receptor tyrosine kinases (RTK) which consists of 14 different receptors which are classed as EphA or EphB. Their ligands, the ephrins, are cell membrane-bound, either via glycosylphosphatidylinositol (GPI)-linkage (ephrin-A ligands) or transmembraneembedded (ephrin-B ligands). Mertens-Walker et al BMC Cancer (2015) 15:164 clinical samples and has been implicated in prostate cancer development and progression [2,7] It has been shown using targeted siRNA sequences that knockdown of EphB4 in prostate cancer causes a significant reduction in cell motility in vitro and tumor growth in vivo [5]. We sought to determine the genome-wide changes upon transient knockdown of EPHB4 in a ligand-independent context in the prostate cancer cell line LNCaP
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