title: Expression and prognostic significance of a comprehensive epithelial-mesenchymal transition gene set in renal cell carcinoma.
abstract: OBJECTIVE
  Epithelial-mesenchymal transition enhances tumor cell motility and has a critical role in invasion and metastasis in a number of carcinomas. A set of transcription factors acts as a master regulator of the epithelial-mesenchymal transition process. To our knowledge it is unknown whether epithelial-mesenchymal transition is important for clear cell renal cell carcinoma progression. Therefore, we comprehensively assessed mRNA levels of epithelial-mesenchymal transition associated genes in renal cell carcinoma as well as their prognostic relevance.
  
  
  METHODS
  We determined the expression of a set of 46 epithelial-mesenchymal transition related genes by oligonucleotide microarray and gene set enrichment analyses using RNA from 14 samples each of normal kidneys, and G1 and G3 primary renal cell carcinomas. Expression of select epithelial-mesenchymal transition genes was validated by real-time polymerase chain reaction in normal kidneys, primary renal cell carcinomas and metastases in an independent cohort of 112 patients. Results were combined with followup data for survival analysis.
  
  
  RESULTS
  The epithelial-mesenchymal transition gene set was preferentially expressed in primary renal cell carcinoma compared to normal tissue (false discovery rate 0.01). No difference was found between G1 and G3 tumors. Quantitative reverse transcriptase-polymerase chain reaction revealed down-regulation of critical epithelial-mesenchymal transition genes such as CDH2 and ZEB1 in metastases, suggesting epithelial-mesenchymal transition reversal during metastasis. Kaplan-Meier analysis demonstrated a better outcome in patients with low CXCR4, vimentin, fibronectin and TWIST1 mRNA levels. Multivariate analyses revealed that CXCR4 and VIM up-regulation represents an independent prognostic marker for poor cancer specific survival in patients with renal cell carcinoma.
  
  
  CONCLUSIONS
  Taken together, our data provide strong evidence that epithelial-mesenchymal transition occurs in renal cell carcinoma. Thus, interference with epithelial-mesenchymal transition in renal cell carcinoma might represent a future therapeutic option.
authors.affiliation: Department of Urology, University Hospital, Munich, Germany; Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, People's Republic of China. Electronic address: dong.chen@med.uni-muenchen.de.
authors.forename: Dong
authors.initials: D
authors.lastname: Chen
authors.affiliation: Tumor Immunology Laboratory, LIFE Center, Munich, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Gassenmaier
authors.affiliation: Department of Urology, University of Rostock, Rostock, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Maruschke
authors.affiliation: Tumor Immunology Laboratory, LIFE Center, Munich, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Riesenberg
authors.affiliation: Tumor Immunology Laboratory, LIFE Center, Munich, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Pohla
authors.affiliation: Department of Urology, University Hospital, Munich, Germany.
authors.forename: Christian G
authors.initials: CG
authors.lastname: Stief
authors.affiliation: Tumor Immunology Laboratory, LIFE Center, Munich, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Zimmermann
authors.affiliation: Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Buchner
mesh_terms: D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D018450:Disease Progression; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D012333:RNA, Messenger / Q000096:biosynthesis; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D012333:RNA, Messenger
keywords: CXC chemokine receptor; CXCR; EMT; ES; FDR; FN1; GSEA; MET; PCR; RCC; TGF-β; VIM; ZEB1; carcinoma; clear cell; enrichment score; epithelial-mesenchymal transition; false discovery rate; fc; fibronectin; fold change; gene expression; gene set enrichment analysis; kidney; mesenchymal-epithelial transition; polymerase chain reaction; prognosis; renal cell carcinoma; transforming growth factor-β; vimentin; zinc finger E-box binding homeobox 1