The tumour-promoting receptor tyrosine kinase, EphB4, regulates expression of Integrin-β8 in prostate cancer cells

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.

PI3 kinase pathway regulated miRNome in glioblastoma: identification of miR-326 as a tumour suppressor miRNA

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Systematic screening identifies a 2‐gene signature as a high‐potential prognostic marker of undifferentiated pleomorphic sarcoma/myxofibrosarcoma

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“…αvβ8 has been detected in tumor cells of various carcinomas, including lung, ovarian, endometrial, melanoma, breast, prostate, colon, skin, and stomach. αvβ8 expression in human cancer cells is involved in the progression of epithelial malignancies; increased αvβ8 expression is also associated with decreased survival in non-small cell lung carcinoma, triplenegative basal-type breast cancer, and advanced ovarian cancer [19][20][21]. Additionally, αvβ8-mediated TGF-β activation regulates tumor immune tolerance, which results in the decreased infiltration of cytotoxic T cells and proinflammatory tumor-associated macrophages to the tumor center [19,22,23].…”