Identifying novel hypoxia-associated markers of chemoresistance in ovarian cancer

Article


McEvoy, L., O'Toole, S., Spillane, C., Martin, C., Gallagher, M., Stordal, B., Blackshields, G., Sheils, O. and O'Leary, J. 2015. Identifying novel hypoxia-associated markers of chemoresistance in ovarian cancer. BMC cancer. 15 (1). https://doi.org/10.1186/s12885-015-1539-8
TypeArticle
TitleIdentifying novel hypoxia-associated markers of chemoresistance in ovarian cancer
AuthorsMcEvoy, L., O'Toole, S., Spillane, C., Martin, C., Gallagher, M., Stordal, B., Blackshields, G., Sheils, O. and O'Leary, J.
Abstract

BACKGROUND
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)-1α. While HIF-1α 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-1α 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.

KeywordsHypoxia; Chemoresistance; Ovarian cancer; Cisplatin; Biomarkers
Research GroupBiomarkers for Cancer group
PublisherBioMed Central
JournalBMC cancer
ISSN1471-2407
Publication dates
Online25 Jul 2015
Print31 Dec 2015
Publication process dates
Deposited08 Jan 2016
Accepted13 Jul 2015
Output statusPublished
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Copyright Statement

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Digital Object Identifier (DOI)https://doi.org/10.1186/s12885-015-1539-8
Web of Science identifierWOS:000358477500003
LanguageEnglish
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