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BMC Cancer. 2012; 12: 91.
Published online Mar 19, 2012. doi:  10.1186/1471-2407-12-91
PMCID: PMC3342883
EMT transcription factors snail and slug directly contribute to cisplatin resistance in ovarian cancer
Alexandria M Haslehurst,1 Madhuri Koti,1 Moyez Dharsee,4 Paulo Nuin,1,4 Ken Evans,1,4 Joseph Geraci,4 Timothy Childs,1 Jian Chen,4 Jieran Li,4 Johanne Weberpals,2 Scott Davey,1 Jeremy Squire,1,3 Paul C Park,1 and Harriet Feilottercorresponding author1,4
1Department of Pathology and Molecular Medicine, Queen's University, 88 Stuart Street, Kingston, ON, K7L3N6, Canada
2Division of Gynaecologic Oncology, The Ottawa Hospital, 501 Smyth Road, Ottawa, ON, K1H8L6, Canada
3NCIC Clinical Trials Group, Cancer Research Institute, 10 Stuart Street, Kingston, ON, K7L3N6, Canada
4Ontario Cancer Biomarker Network, 101 College Street, Toronto, ON, M5G 1L7, Canada
corresponding authorCorresponding author.
Alexandria M Haslehurst: 9ah33/at/queensu.ca; Madhuri Koti: madhurikoti/at/gmail.com; Moyez Dharsee: mdharsee/at/ocbn.ca; Paulo Nuin: nuin/at/genedrift.org; Ken Evans: kevans/at/ocbn.ca; Joseph Geraci: jgeraci/at/ocbn.ca; Timothy Childs: childst2/at/kgh.kari.net; Jian Chen: jchen/at/ocbn.ca; Jieran Li: jli/at/ocbn.ca; Johanne Weberpals: jweberpals/at/ottawahospital.on.ca; Scott Davey: scott.davey/at/queensu.ca; Jeremy Squire: squirej/at/queensu.ca; Paul C Park: pcpark/at/gmail.com; Harriet Feilotter: feilotth/at/kgh.kari.net
Received December 13, 2011; Accepted March 19, 2012.
Abstract
Background
The epithelial to mesenchymal transition (EMT) is a molecular process through which an epithelial cell undergoes transdifferentiation into a mesenchymal phenotype. The role of EMT in embryogenesis is well-characterized and increasing evidence suggests that elements of the transition may be important in other processes, including metastasis and drug resistance in various different cancers.
Methods
Agilent 4 × 44 K whole human genome arrays and selected reaction monitoring mass spectrometry were used to investigate mRNA and protein expression in A2780 cisplatin sensitive and resistant cell lines. Invasion and migration were assessed using Boyden chamber assays. Gene knockdown of snail and slug was done using targeted siRNA. Clinical relevance of the EMT pathway was assessed in a cohort of primary ovarian tumours using data from Affymetrix GeneChip Human Genome U133 plus 2.0 arrays.
Results
Morphological and phenotypic hallmarks of EMT were identified in the chemoresistant cells. Subsequent gene expression profiling revealed upregulation of EMT-related transcription factors including snail, slug, twist2 and zeb2. Proteomic analysis demonstrated up regulation of Snail and Slug as well as the mesenchymal marker Vimentin, and down regulation of E-cadherin, an epithelial marker. By reducing expression of snail and slug, the mesenchymal phenotype was largely reversed and cells were resensitized to cisplatin. Finally, gene expression data from primary tumours mirrored the finding that an EMT-like pathway is activated in resistant tumours relative to sensitive tumours, suggesting that the involvement of this transition may not be limited to in vitro drug effects.
Conclusions
This work strongly suggests that genes associated with EMT may play a significant role in cisplatin resistance in ovarian cancer, therefore potentially leading to the development of predictive biomarkers of drug response or novel therapeutic strategies for overcoming drug resistance.
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