title: EMT transcription factors snail and slug directly contribute to cisplatin resistance in ovarian cancer.
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.
authors.affiliation: Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada.
authors.forename: Alexandria M
authors.initials: AM
authors.lastname: Haslehurst
authors.forename: Madhuri
authors.initials: M
authors.lastname: Koti
authors.forename: Moyez
authors.initials: M
authors.lastname: Dharsee
authors.forename: Paulo
authors.initials: P
authors.lastname: Nuin
authors.forename: Ken
authors.initials: K
authors.lastname: Evans
authors.forename: Joseph
authors.initials: J
authors.lastname: Geraci
authors.forename: Timothy
authors.initials: T
authors.lastname: Childs
authors.forename: Jian
authors.initials: J
authors.lastname: Chen
authors.forename: Jieran
authors.initials: J
authors.lastname: Li
authors.forename: Johanne
authors.initials: J
authors.lastname: Weberpals
authors.forename: Scott
authors.initials: S
authors.lastname: Davey
authors.forename: Jeremy
authors.initials: J
authors.lastname: Squire
authors.forename: Paul C
authors.initials: PC
authors.lastname: Park
authors.forename: Harriet
authors.initials: H
authors.lastname: Feilotter
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002945:Cisplatin / Q000627:therapeutic use*; D015331:Cohort Studies; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D013058:Mass Spectrometry / Q000379:methods; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D012333:RNA, Messenger; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D002945:Cisplatin