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dc.contributor.authorSHEILS, ORLAen
dc.contributor.authorO'LEARY, JOHNen
dc.contributor.authorGALLAGHER, MICHAELen
dc.contributor.authorSPILLANE, CATHYen
dc.date.accessioned2017-02-02T15:10:21Z
dc.date.available2017-02-02T15:10:21Z
dc.date.issued2015en
dc.date.submitted2015en
dc.identifier.citationMcEvoy, L.M., O'Toole, S.A., Spillane, C.D., Martin, C.M., Gallagher, M.F., Stordal, B., Blackshields, G., Sheils, O., O'Leary, J.J., Identifying novel hypoxia-associated markers of chemoresistance in ovarian cancer, BMC Cancer, 15, 1, 2015, 547-en
dc.identifier.otherYen
dc.identifier.urihttp://hdl.handle.net/2262/79191
dc.descriptionPUBLISHEDen
dc.description.abstractBackground: Ovarian cancer is associated with poor long-term survival due to late diagnosis and development of chemoresistance. Tumour hypoxia is associated with many features of tumour aggressiveness including increased cellular proliferation, inhibition of apoptosis, increased invasion and metastasis, and chemoresistance, mostly mediated through hypoxia-inducible factor (HIF)-1aα. While HIF-1aα has been associated with platinum resistance in a variety of cancers, including ovarian, relatively little is known about the importance of the duration of hypoxia. Similarly, the gene pathways activated in ovarian cancer which cause chemoresistance as a result of hypoxia are poorly understood. This study aimed to firstly investigate the effect of hypoxia duration on resistance to cisplatin in an ovarian cancer chemoresistance cell line model and to identify genes whose expression was associated with hypoxia-induced chemoresistance. Methods: Cisplatin-sensitive (A2780) and cisplatin-resistant (A2780cis) ovarian cancer cell lines were exposed to various combinations of hypoxia and/or chemotherapeutic drugs as part of a 'hypoxia matrix' designed to cover clinically relevant scenarios in terms of tumour hypoxia. Response to cisplatin was measured by the MTT assay. RNA was extracted from cells treated as part of the hypoxia matrix and interrogated on Affymetrix Human Gene ST 1.0 arrays. Differential gene expression analysis was performed for cells exposed to hypoxia and/or cisplatin. From this, four potential markers of chemoresistance were selected for evaluation in a cohort of ovarian tumour samples by RT-PCR. Results: Hypoxia increased resistance to cisplatin in A2780 and A2780cis cells. A plethora of genes were differentially expressed in cells exposed to hypoxia and cisplatin which could be associated with chemoresistance. In ovarian tumour samples, we found trends for upregulation of ANGPTL4 in partial responders and down-regulation in non-responders compared with responders to chemotherapy; down-regulation of HER3 in partial and non-responders compared to responders; and down-regulation of HIF-1aα in non-responders compared with responders. Conclusion: This study has further characterized the relationship between hypoxia and chemoresistance in an ovarian cancer model. We have also identified many potential biomarkers of hypoxia and platinum resistance and provided an initial validation of a subset of these markers in ovarian cancer tissues.en
dc.description.sponsorshipThe authors would like to thank the Emer Casey Foundation for providing the funding for this project. The authors would also like to thank Mr A McGoldrick for preparation of FFPE sections for analysisen
dc.format.extent547en
dc.language.isoenen
dc.relation.ispartofseriesBMC Canceren
dc.relation.ispartofseries15en
dc.relation.ispartofseries1en
dc.rightsYen
dc.subjectOvarian canceren
dc.subject.lcshOvarian canceren
dc.titleIdentifying novel hypoxia-associated markers of chemoresistance in ovarian canceren
dc.typeJournal Articleen
dc.type.supercollectionscholarly_publicationsen
dc.type.supercollectionrefereed_publicationsen
dc.identifier.peoplefinderurlhttp://people.tcd.ie/osheilsen
dc.identifier.peoplefinderurlhttp://people.tcd.ie/cspillaen
dc.identifier.peoplefinderurlhttp://people.tcd.ie/olearyjjen
dc.identifier.peoplefinderurlhttp://people.tcd.ie/gallagmien
dc.identifier.rssinternalid109886en
dc.identifier.doihttp://dx.doi.org/10.1186/s12885-015-1539-8en
dc.rights.ecaccessrightsopenAccess
dc.subject.TCDThemeCanceren
dc.identifier.orcid_id0000-0002-4493-9496en
dc.subject.darat_thematicHealthen
dc.status.accessibleNen


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