SIX1 promotes epithelial-mesenchymal transition in colorectal cancer through ZEB1 activation

Oncogene. 2012 Nov 22;31(47):4923-34. doi: 10.1038/onc.2011.646. Epub 2012 Jan 30.


Epithelial-mesenchymal transition (EMT) has a major role in cancer progression, as well as normal organ development and human pathology such as organ fibrosis and wound healing. Here, we performed a gene expression array specialized in EMT of colorectal cancer (CRC). From a comprehensive gene expression analysis using epithelial- and mesenchymal-like CRC cell lines, and following the ontology (GO) analysis, SIX1 gene was identified to be an EMT-related gene in CRC. Using SW480 cells stably transfected with a SIX1 expression construct and their control counterparts, we demonstrated that SIX1 overexpression represses CDH1 expression and promotes EMT in CRC. SIX1-induced CDH1 repression and EMT in CRC cells were correlated at least in part with posttranscriptional ZEB1 activation and miR-200-family transcriptional repression. In primary tumors of CRC, in accord with the functional findings, aberrant expression of SIX1 in cancer cells was observed at the disruption of the basement membrane and at the tumor invasive front, where tumor cells underwent EMT in vivo. Taken together, SIX1 overexpression is suggested to occur in carcinogenesis, and contribute to repression of CDH1 expression and promotion of EMT partly through repression of miR-200-family expression and activation of ZEB1 in CRC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD
  • Cadherins / genetics
  • Cadherins / metabolism
  • Cell Line, Tumor
  • Cell Movement
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / mortality
  • Colorectal Neoplasms / pathology
  • Epithelial-Mesenchymal Transition / genetics*
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Homeodomain Proteins / physiology*
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • Middle Aged
  • Oligonucleotide Array Sequence Analysis
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic
  • Transcriptome
  • Zinc Finger E-box-Binding Homeobox 1


  • Antigens, CD
  • CDH1 protein, human
  • Cadherins
  • Homeodomain Proteins
  • MIRN200 microRNA, human
  • MicroRNAs
  • SIX1 protein, human
  • Transcription Factors
  • ZEB1 protein, human
  • Zinc Finger E-box-Binding Homeobox 1