Identifying novel hypoxia-associated markers of chemoresistance in ovarian cancer

BMC Cancer

Research Article

Britta Stordal¹  Gordon Blackshields¹  Orla Sheils¹  Lynda M. McEvoy²  John J. O’Leary³  Sharon A. O’Toole⁴  Cathy D. Spillane⁵  Cara M. Martin⁵  Michael F. Gallagher⁵ 

[1] Department of Histopathology TCD, Sir Patrick Dun’s Laboratory, Central Pathology Laboratory, St James’s Hospital, Dublin 8, Ireland;Department of Histopathology TCD, Sir Patrick Dun’s Laboratory, Central Pathology Laboratory, St James’s Hospital, Dublin 8, Ireland;Department of Obstetrics and Gynaecology, Trinity Centre for Health Sciences, St James’s Hospital, Dublin 8, Ireland;Department of Histopathology TCD, Sir Patrick Dun’s Laboratory, Central Pathology Laboratory, St James’s Hospital, Dublin 8, Ireland;Molecular Pathology Laboratory, Coombe Women and Infants’ University Hospital, Dublin 8, Ireland;Department of Obstetrics and Gynaecology, Trinity Centre for Health Sciences, St James’s Hospital, Dublin 8, Ireland;Molecular Pathology Laboratory, Coombe Women and Infants’ University Hospital, Dublin 8, Ireland;

关键词: Hypoxia;    Chemoresistance;    Ovarian cancer;    Cisplatin;    Biomarkers;   

DOI  :  10.1186/s12885-015-1539-8

 received in 2014-11-04, accepted in 2015-07-13,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundOvarian 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.MethodsCisplatin-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.ResultsHypoxia 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.ConclusionThis 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.

【 授权许可】

CC BY   
© McEvoy et al. 2015