Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2015

Open Access 01-12-2015 | Research article

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

Authors: Inga Mertens-Walker, Bruno C Fernandini, Mohanan SN Maharaj, Anja Rockstroh, Colleen C Nelson, Adrian C Herington, Sally-Anne Stephenson

Published in: BMC Cancer | Issue 1/2015

Login to get access

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.
Appendix
Available only for authorised users
Literature
1.
Pasquale EB. Eph receptor signalling casts a wide net on cell behaviour. Nat Rev Mol Cell Biol. 2005;6:462–75.CrossRefPubMed
2.
Rutkowski R, Mertens-Walker I, Lisle JE, Herington AC, Stephenson SA. Evidence for a dual function of EphB4 as tumor promoter and suppressor regulated by the absence or presence of the ephrin-B2 ligand. Int J Cancer. 2012;131:E614–24.CrossRefPubMed
3.
Dopeso H, Mateo-Lozano S, Mazzolini R, Rodrigues P, Lagares-Tena L, Ceron J, et al. The receptor tyrosine kinase EPHB4 has tumor suppressor activities in intestinal tumorigenesis. Cancer Res. 2009;69:7430–8.CrossRefPubMed
4.
Kumar SR, Singh J, Xia G, Krasnoperov V, Hassanieh L, Ley EJ, et al. Receptor tyrosine kinase EphB4 is a survival factor in breast cancer. Am J Pathol. 2006;169:279–93.CrossRefPubMedPubMedCentral
5.
Xia G, Kumar SR, Masood R, Zhu S, Reddy R, Krasnoperov V, et al. EphB4 expression and biological significance in prostate cancer. Cancer Res. 2005;65:4623–32.CrossRefPubMed
6.
Noren NK, Foos G, Hauser CA, Pasquale EB. The EphB4 receptor suppresses breast cancer cell tumorigenicity through an Abl-Crk pathway. Nat Cell Biol. 2006;8:815–25.CrossRefPubMed
7.
Lee YC, Perren JR, Douglas EL, Raynor MP, Bartley MA, Bardy PG, et al. Investigation of the expression of the EphB4 receptor tyrosine kinase in prostate carcinoma. BMC cancer. 2005;5:119.CrossRefPubMedPubMedCentral
8.
Sieh S, Taubenberger AV, Rizzi SC, Sadowski M, Lehman ML, Rockstroh A, et al. Phenotypic characterization of prostate cancer LNCaP cells cultured within a bioengineered microenvironment. PloS One. 2012;7:e40217.CrossRefPubMedPubMedCentral
9.
Stephenson SA, Slomka S, Douglas EL, Hewett PJ, Hardingham JE. Receptor protein tyrosine kinase EphB4 is up-regulated in colon cancer. BMC Mol Biol. 2001;2:15.CrossRefPubMedPubMedCentral
10.
Nishimura SL, Sheppard D, Pytela R. Integrin alpha v beta 8. Interaction with vitronectin and functional divergence of the beta 8 cytoplasmic domain. J Biol Chem. 1994;269:28708–15.PubMed
11.
Reyes SB, Narayanan AS, Lee HS, Tchaicha JH, Aldape KD, Lang FF, et al. Alphavbeta8 integrin interacts with RhoGDI1 to regulate Rac1 and Cdc42 activation and drive glioblastoma cell invasion. Mol Biol Cell. 2013;24:474–82.CrossRefPubMedPubMedCentral
12.
Thalmann GN, Anezinis PE, Chang SM, Zhau HE, Kim EE, Hopwood VL, et al. Androgen-independent cancer progression and bone metastasis in the LNCaP model of human prostate cancer. Cancer Res. 1994;54:2577–81.PubMed
13.
Tomlins SA, Mehra R, Rhodes DR, Cao X, Wang L, Dhanasekaran SM, et al. Integrative molecular concept modeling of prostate cancer progression. Nat Genet. 2007;39:41–51.CrossRefPubMed
14.
15.
Walsh R, Blumenberg M. Eph-2B, acting as an extracellular ligand, induces differentiation markers in epidermal keratinocytes. J Cell Physiol. 2012;227:2330–40.CrossRefPubMed
16.
17.
18.
Weis SM, Cheresh DA. Tumor angiogenesis: molecular pathways and therapeutic targets. Nat Med. 2011;17:1359–70.CrossRefPubMed
19.
Jülich D, Mould AP, Koper E, Holley SA. Control of extracellular matrix assembly along tissue boundaries via integrin and Eph/Ephrin signaling. Development. 2009;136:2913–21.CrossRefPubMed
20.
Bourgin C, Murai KK, Richter M, Pasquale EB. The EphA4 receptor regulates dendritic spine remodeling by affecting beta1-integrin signaling pathways. J Cell Biol. 2007;178:1295–307.CrossRefPubMedPubMedCentral
21.
Zou JX, Wang B, Kalo MS, Zisch AH, Pasquale EB, Ruoslahti E. An Eph receptor regulates integrin activity through R-Ras. Proc Natl Acad Sci U S A. 1999;96:13813–8.CrossRefPubMedPubMedCentral
22.
Makarov A, Ylivinkka I, Nyman TA, Hyytiainen M, Keski-Oja J. Ephrin-As, Eph receptors and integrin alpha3 interact and colocalise at membrane protrusions of U251MG glioblastoma cells. Cell Biol Int. 2013;37:1090–88.CrossRef
23.
Noren NK, Yang NY, Silldorff M, Mutyala R, Pasquale EB. Ephrin-independent regulation of cell substrate adhesion by the EphB4 receptor. Biochem J. 2009;422:433–42.CrossRefPubMedPubMedCentral
24.
Markovics JA, Araya J, Cambier S, Jablons D, Hill A, Wolters PJ, et al. Transcription of the transforming growth factor beta activating integrin beta8 subunit is regulated by SP3, AP-1, and the p38 pathway. J Biol Chem. 2010;285:24695–706.CrossRefPubMedPubMedCentral
25.
Bruhl T, Urbich C, Aicher D, Acker-Palmer A, Zeiher AM, Dimmeler S. Homeobox A9 transcriptionally regulates the EphB4 receptor to modulate endothelial cell migration and tube formation. Circ Res. 2004;94:743–51.CrossRefPubMed
26.
Liu LX, Jiang HC, Liu ZH, Zhou J, Zhang WH, Zhu AL, et al. Integrin gene expression profiles of human hepatocellular carcinoma. World J Gastroenterol. 2002;8:631–7.CrossRefPubMedPubMedCentral
27.
Goodman SL, Grote HJ, Wilm C. Matched rabbit monoclonal antibodies against alphav-series integrins reveal a novel alphavbeta3-LIBS epitope, and permit routine staining of archival paraffin samples of human tumors. Biol Open. 2012;1:329–40.CrossRefPubMedPubMedCentral
28.
Vogetseder A, Thies S, Ingold B, Roth P, Weller M, Schraml P, et al. Alphav-Integrin isoform expression in primary human tumors and brain metastases. Int J Cancer. 2013;133:2362–71.CrossRefPubMed
29.
Landemaine T, Jackson A, Bellahcene A, Rucci N, Sin S, Abad BM, et al. A six-gene signature predicting breast cancer lung metastasis. Cancer Res. 2008;68:6092–9.CrossRefPubMed
30.
Cambier S, Mu D-Z, O’Connell D, Boylen K, Travis W, Liu W-H, et al. A Role for the Integrin αvβ8 in the negative regulation of epithelial cell growth. Cancer Res. 2000;60:7084–93.PubMed
31.
Xu Z, Wu R. Alteration in metastasis potential and gene expression in human lung cancer cell lines by ITGB8 silencing. Anat Rec (Hoboken). 2012;295:1446–54.CrossRef
32.
Fang L, Deng Z, Shatseva T, Yang J, Peng C, Du WW, et al. MicroRNA miR-93 promotes tumor growth and angiogenesis by targeting integrin-beta8. Oncogene. 2011;30:806–21.CrossRefPubMed
33.
Astin JW, Batson J, Kadir S, Charlet J, Persad RA, Gillatt D, et al. Competition amongst Eph receptors regulates contact inhibition of locomotion and invasiveness in prostate cancer cells. Nat Cell Biol. 2010;12:1194–204.CrossRefPubMed
34.
Nishimura SL. Integrin-mediated transforming growth factor-beta activation, a potential therapeutic target in fibrogenic disorders. Am J Pathol. 2009;175:1362–70.CrossRefPubMedPubMedCentral
35.
Juarez P, Guise TA. TGF-beta in cancer and bone: implications for treatment of bone metastases. Bone. 2011;48:23–9.CrossRefPubMed
36.
Jones E, Pu H, Kyprianou N. Targeting TGF-beta in prostate cancer: therapeutic possibilities during tumor progression. Expert Opin Ther Targets. 2009;13:227–34.CrossRefPubMed
37.
Eisele G, Wick A, Eisele AC, Clement PM, Tonn J, Tabatabai G, et al. Cilengitide treatment of newly diagnosed glioblastoma patients does not alter patterns of progression. J Neurooncol. 2014;117:141–5.CrossRefPubMed
38.
Vermorken JB, Peyrade F, Krauss J, Mesia R, Remenar E, Gauler TC, et al. Cisplatin, 5-fluorouracil, and cetuximab (PFE) with or without cilengitide in recurrent/metastatic squamous cell carcinoma of the head and neck: results of the randomized phase I/II ADVANTAGE trial (phase II part). Ann Oncol. 2014;25:682–8.CrossRefPubMedPubMedCentral
39.
Manegold C, Vansteenkiste J, Cardenal F, Schuette W, Woll PJ, Ulsperger E, et al. Randomized phase II study of three doses of the integrin inhibitor cilengitide versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer. Invest New Drugs. 2013;31:175–82.CrossRefPubMed
40.
Alva A, Slovin S, Daignault S, Carducci M, Dipaola R, Pienta K, et al. Phase II study of cilengitide (EMD 121974, NSC 707544) in patients with non-metastatic castration resistant prostate cancer, NCI-6735. A study by the DOD/PCF prostate cancer clinical trials consortium. Invest New Drugs. 2012;30:749–57.CrossRefPubMed
Metadata
Title
The tumour-promoting receptor tyrosine kinase, EphB4, regulates expression of Integrin-β8 in prostate cancer cells
Authors
Inga Mertens-Walker
Bruno C Fernandini
Mohanan SN Maharaj
Anja Rockstroh
Colleen C Nelson
Adrian C Herington
Sally-Anne Stephenson
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2015
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-015-1164-6

Other articles of this Issue 1/2015

BMC Cancer 1/2015 Go to the issue

Research article

Coffee consumption and the risk of gastric cancer: a meta-analysis of prospective cohort studies

Research article

Role of baseline echocardiography prior to initiation of anthracycline-based chemotherapy in breast cancer patients

Research article

CD147 expression predicts biochemical recurrence after prostatectomy independent of histologic and pathologic features

Research article

Protein Kinase A-induced tamoxifen resistance is mediated by anchoring protein AKAP13

Research article

Attitudes and practice patterns for maintaining relative dose intensity of chemotherapy in outpatient clinics: results of a Japanese web-based survey

Research article

Clonal distribution of BCR-ABL1 mutations and splice isoforms by single-molecule long-read RNA sequencing
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits