title: The tumour-promoting receptor tyrosine kinase, EphB4, regulates expression of integrin-β8 in prostate cancer cells.
abstract: 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 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.
  
  
  CONCLUSIONS
  These 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.
authors.affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, 37 Kent Street, Woolloongabba, Queensland, 4102, Australia. inga.mertenswalker@qut.edu.au.|Australian Prostate Cancer Research Centre - Queensland, Princess Alexandra Hospital, Woolloongabba, Queensland, 4102, Australia. inga.mertenswalker@qut.edu.au.
authors.forename: Inga
authors.initials: I
authors.lastname: Mertens-Walker
authors.affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, 37 Kent Street, Woolloongabba, Queensland, 4102, Australia. fern0082@uni.flinders.edu.au.
authors.forename: Bruno C
authors.initials: BC
authors.lastname: Fernandini
authors.affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, 37 Kent Street, Woolloongabba, Queensland, 4102, Australia. mohanan.maharaj@hdr.qut.edu.au.
authors.forename: Mohanan S N
authors.initials: MS
authors.lastname: Maharaj
authors.affiliation: Australian Prostate Cancer Research Centre - Queensland, Princess Alexandra Hospital, Woolloongabba, Queensland, 4102, Australia. anja.rockstroh@qut.edu.au.
authors.forename: Anja
authors.initials: A
authors.lastname: Rockstroh
authors.affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, 37 Kent Street, Woolloongabba, Queensland, 4102, Australia. colleen.nelson@qut.edu.au.|Australian Prostate Cancer Research Centre - Queensland, Princess Alexandra Hospital, Woolloongabba, Queensland, 4102, Australia. colleen.nelson@qut.edu.au.
authors.forename: Colleen C
authors.initials: CC
authors.lastname: Nelson
authors.affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, 37 Kent Street, Woolloongabba, Queensland, 4102, Australia. a.herington@qut.edu.au.|Australian Prostate Cancer Research Centre - Queensland, Princess Alexandra Hospital, Woolloongabba, Queensland, 4102, Australia. a.herington@qut.edu.au.
authors.forename: Adrian C
authors.initials: AC
authors.lastname: Herington
authors.affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, 37 Kent Street, Woolloongabba, Queensland, 4102, Australia. s.stephenson@qut.edu.au.|Australian Prostate Cancer Research Centre - Queensland, Princess Alexandra Hospital, Woolloongabba, Queensland, 4102, Australia. s.stephenson@qut.edu.au.
authors.forename: Sally-Anne
authors.initials: SA
authors.lastname: Stephenson
mesh_terms: D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039641:Integrin beta Chains / Q000096:biosynthesis*; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology; D036224:Receptor, EphB4 / Q000502:physiology*
chemical_list: D039641:Integrin beta Chains; C094865:integrin beta8; D020794:Receptor Protein-Tyrosine Kinases; D036224:Receptor, EphB4