5. The role of the miR-200 family of microRNAs and its targets in epithelial/ mesenchymal transition (EMT) and tumor progression.

 

Micro (mi)RNAs are small 20-22 nucleotide (nt) long non-coding RNAs that inhibit gene expression at the posttranscriptional level. Each of the approximately 400 miRNAs known to exist in mammalian cells has multiple targets making them powerful regulators of complex processes such as differentiation and cancer progression. Indeed a strong link between miRNA and human cancers has been established as miRNAs have been demonstrated to either act as oncogenes (e.g. miR-155, miR-17-5p, miR-21) or tumor suppressors (e.g. miR-15a, miR-16-1, let-7) (1,2).

Epithelial to mesenchymal transition (EMT)-like processes occur as part of the embryonic development, wound healing, and during carcinogenesis when cancer cells undergo a change from a differentiated to a more invasive dedifferentiated tumor. After EMT induction, cells lose epithelial features and acquire mesenchymal characteristics, including Vimentin filaments and a flattened phenotype. They become more invasive by expressing proteases that allow them to pass through the underlying basement membrane and to migrate both being crucial steps in the multi step process of metastasis.

By evaluating the expression of 207 miRNAs in the 60 cell lines of the drug screening panel maintained by the Nation Cancer Institute (3) the miR-200 miRNA family was identified as an extraordinary marker for epithelial cells that express E-cadherin but lack expression of Vimentin (4). These findings were extended to primary ovarian cancer specimens. miR-200 was found to directly target the mRNA of the E-cadherin transcriptional repressors ZEB1 (TCF8/dEF1) and ZEB2 (SIP1/ZFXH1B). Ectopic expression of miR-200 caused upregulation of E-cadherin in cancer cell lines and reduced their motility. Conversely, inhibition of miR-200 reduced E-cadherin expression, increased expression of Vimentin and induced EMT.

Based on these data the following model for the function of the miR-200 family in EMT and cancer progression is proposed: In epithelial cancer cells and well differentiated cancers miR-200 is highly expressed controlling the expression of ZEB1 and ZEB2. Other mechanisms cause induction of E-cadherin expression and suppression of Vimentin expression. In contrast when miR-200 expression is either downregulated (in mesenchymal cancer cells or in tissues undergoing EMT) ZEB1 and ZEB2 proteins are expressed. Both ZEB1 and ZEB2 are strong suppressors of E-cadherin expression. At the same time ZEB2 has been shown to directly activate the Vimentin promoter by an unknown mechanism causing Vimentin to be expressed. The data have identified miR-200 as a powerful master regulator of EMT in cancer cells and suggest that introducing miR-200 into cancer cells could be a novel way of reversing tumor progression.

References

1.	Park, S.-M. and Peter, M.E. (2008) microRNAs and death receptors. Cytokine Growth Factor Rev, in press.
2.	Schickel, R., Boyerinas, B., Park, S.-M. and Peter, M.E. (2008) MicroRNAs: keyplayers in the immune system, differentiation, tumorigenesis and cell death. Oncogene, in press.
3.	Shell, S., Park, S.-M., Radjabi, A.R., Schickel, R., Kistner, E.O., Jewell, D.A., Feig, C., Lengyel, E. and Peter, M.E. (2007) Let-7 expression defines two differentiation stages of cancer. Proc. Natl. Acad. Sci. USA, 104:11400-11405.
4.	Park, S.-M., Gaur, A.B., Lengyel, E. and Peter, M.E. (2008) The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors, ZEB1 and ZEB2. Genes Dev. 22, 894-907 . Press release by Cold Spring Harbor Press on March 31, 2008: "MicroRNAs, EMT and Cancer Progression". N&V in Nature Cell Biology, May 2008: "miRNAs - keeping cells in formation". News coverage in: Arcor, Bio-Medicine, BioToday, ChekBiotech, City Helath Newws, CSHL Press, Drug Cancer, EurekAlert, First Sciene, GEN, Google-Sina, Health0Fitness, Inovations Report, MedFeeds, MedicalUsers, MedStore, MyCancerRisks, News-Medical, Newstin, Newswise Medical News, Newsweek, Physorg, Revista Pesquisa Medica, Science Centric, Science Codex, Science Daily, Silobreakr, The University of Chicago, Think Gene, YourLabData and others.