Downregulation of Genes Contributes to Chemoresistance Induced by Hypoxia
Lynda M McEvoy, Sharon A O'Toole, Cathy D Spillane, Cara M Martin, Orla Sheils, John J O'Leary. Trinity College Dublin, Dublin, Ireland
Background: Ovarian cancer is the leading cause of death from gynaecological malignancy in the Western world. This is in part due to tumours which become chemoresistant. There are many causes of chemoresistance, including hypoxia. Hypoxia is characterised as a low level of oxygen tension within tumours. It induces expression of genes involved in chemoresistance mainly via HIF1α. We wanted to investigate the genetic changes induced by hypoxia in an ovarian cancer model, and determine which genes were likely to contribute to chemoresistance. To do this we first compared gene expression between a parent cell line and its daughter chemoresistant line. We subsequently compared these changes to those induced in the parent cell line when it was exposed to hypoxia.
Design: Two ovarian cancer cell lines, A2780 (cisplatin sensitive) and A2780cis (cisplatin resistant) were grown either in normal oxygen conditions (21%O2) or in hypoxia (5%O2) for 72 hours. Total RNA was extracted and run on Affymetrix Human Gene arrays. Data was analysed using X-Ray software (Biotique Systems) and the DAVID functional annotation tool. Genes with a fold-change >2 and with an FDR <0.05 were determined significant.
Results: 1026 genes were altered in A2780cis compared to A2780 cells. Of these, 46 genes were also dysregulated in A2780s when exposed to hypoxia. 29 genes were downregulated in both A2780cis and hypoxic A2780s. These included genes whose suppression is involved in tumorigenesis such as CTH as well as genes with putative tumor suppressor function such as FOXO1, HECA and TXNIP. Expression of genes specifically linked to chemoresistance such as PLK2 were also reduced by hypoxia.
Conclusions: Identification of genes which are involved in both the hypoxic response as well as an induced chemoresistant phenotype sheds light on how chemoresistance is being induced via hypoxia. Interestingly, most of the shared expression changes were downregulation of genes. This may be due to repressor functions of HIF1α or other methods of gene downregulation such as methylation. Identification of these genes may provide novel targets for gene therapy in ovarian cancer patients.
Category: Special Category - Pan-genomic/Pan-proteomic approaches to Cancer
Tuesday, March 20, 2012 9:30 AM
Poster Session III # 289, Tuesday Morning