Email updates

Keep up to date with the latest news and content from BMC Cancer and BioMed Central.

Open Access Highly Accessed Research article

EMT transcription factors snail and slug directly contribute to cisplatin resistance in ovarian cancer

Alexandria M Haslehurst1, Madhuri Koti1, Moyez Dharsee4, Paulo Nuin14, Ken Evans14, Joseph Geraci4, Timothy Childs1, Jian Chen4, Jieran Li4, Johanne Weberpals2, Scott Davey1, Jeremy Squire13, Paul C Park1 and Harriet Feilotter14*

Author Affiliations

1 Department of Pathology and Molecular Medicine, Queen's University, 88 Stuart Street, Kingston, ON, K7L3N6, Canada

2 Division of Gynaecologic Oncology, The Ottawa Hospital, 501 Smyth Road, Ottawa, ON, K1H8L6, Canada

3 NCIC Clinical Trials Group, Cancer Research Institute, 10 Stuart Street, Kingston, ON, K7L3N6, Canada

4 Ontario Cancer Biomarker Network, 101 College Street, Toronto, ON, M5G 1L7, Canada

For all author emails, please log on.

BMC Cancer 2012, 12:91  doi:10.1186/1471-2407-12-91

Published: 19 March 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.