Regulation of miR-200 family microRNAs and ZEB transcription factors in ovarian cancer: evidence supporting a mesothelial-to-epithelial transition

Gynecol Oncol. 2010 Jan;116(1):117-25. doi: 10.1016/j.ygyno.2009.08.009. Epub 2009 Oct 24.


Objective: Our objective was to characterize the expression and function of the miR-200 family of microRNAs (miRNA) in ovarian carcinogenesis.

Methods: We used qRT-PCR to examine expression of the miR-200 miRNA family and its predicted targets, the ZEB1 and ZEB2 transcriptional repressors, in primary cultures of normal cells from the surface of the ovary and in a panel of 70 ovarian cancer tissues and 15 ovarian cancer cell lines. We studied the mechanisms of regulation of miR-200 miRNAs and ZEB transcription factors in ovarian cells using 3' UTR luciferase reporters, promoter luciferase reporters and siRNAs.

Results: miR-200 family members are expressed at low or negligible levels in normal ovarian surface cells and substantially increase in expression in ovarian cancer, whereas expression of ZEB1 and ZEB2 shows the opposite pattern. There is reciprocal repression between miR-200 family members and ZEB transcription factors, creating a double negative regulatory feedback loop resembling that reported in other cancer cell types. In contrast to epithelial cells from other sites, expression levels of miR-200 miRNAs and ZEB1/2 in cells from the ovarian surface are more consistent with a mesenchymal cell phenotype, potentially reflecting the mesothelial origin of the ovarian surface.

Conclusion: Analysis of ovarian cancer tissues suggests that ovarian surface cells acquire a more epithelial miR-200-ZEB1/2 phenotype as they undergo transformation, switching from a miR-200 familyLOW and ZEB1/2HIGH state to a miR-200 familyHIGH and ZEB1/2LOW phenotype. Collectively, our data support the mesothelial-to-epithelial (Meso-E-T) model for development of ovarian cancers that arise from ovarian surface cells, as has been proposed previously on the basis of studies of protein markers.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Epithelial Cells / pathology
  • Epithelium / pathology
  • Female
  • Gene Expression Regulation, Neoplastic
  • Homeodomain Proteins / biosynthesis*
  • Homeodomain Proteins / genetics
  • Humans
  • MicroRNAs / biosynthesis*
  • MicroRNAs / genetics
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology
  • Repressor Proteins / biosynthesis*
  • Repressor Proteins / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription Factors / biosynthesis*
  • Transcription Factors / genetics
  • Zinc Finger E-box Binding Homeobox 2
  • Zinc Finger E-box-Binding Homeobox 1


  • Homeodomain Proteins
  • MicroRNAs
  • Repressor Proteins
  • Transcription Factors
  • ZEB1 protein, human
  • ZEB2 protein, human
  • Zinc Finger E-box Binding Homeobox 2
  • Zinc Finger E-box-Binding Homeobox 1