The miR-200 Family Inhibits Epithelial-Mesenchymal Transition and Cancer Cell Migration by Direct Targeting of E-cadherin Transcriptional Repressors ZEB1 and ZEB2*

By M. Korpal, Esther S. Lee, G. Hu, Yibin Kang. Journal of Biological Chemistry, 2008

1,711 citations recorded by the source corpus.

MicroRNAs are small non-coding RNA molecules that can regulate gene expression by interacting with multiple mRNAs and inducing either translation suppression or degradation of mRNA. Recently, several miRNAs were identified as either promoters or suppressors of metastasis. However, it is unclear in which step(s) of the multistep metastatic cascade these miRNAs play a defined functional role. To study the functional importance of miRNAs in epithelial-mesenchymal transition (EMT), a process thought to initiate metastasis by enhancing the motility of tumor cells, we used a well established in vitro EMT assay: transforming growth factor-β-induced EMT in NMuMG murine mammary epithelial cells. We found that members of the miR-200 family, organized as two clusters in the genome, were repressed during EMT. Overexpression of each miRNA individually or as clusters in NMuMG cells hindered EMT by enhancing E-cadherin expression through direct targeting of ZEB1 and ZEB2, which encode transcriptional repressors of E-cadherin. In the 4TO7 mouse carcinoma cell line, which expresses low levels of endogenous E-cadherin and displays a mesenchymal phenotype, ectopic expression of the miR-200 family miRNAs significantly increased E-cadherin expression and altered cell morphology to an epithelial phenotype. Furthermore, ectopic expression of each miR-200 miRNA cluster significantly reduced the in vitro motility of 4TO7 cells in migration assays. These results suggested that loss of expression of the miR-200 family members may play a critical role in the repression of E-cadherin by ZEB1 and ZEB2 during EMT, thereby enhancing migration and invasion during cancer progression.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/da3cc3e98cf00a5ca696cf736f91c53dc24f1005

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Citations in the corpus

microRNAs in cancer (2013, background): “Furthermore, loss of miR-200 family members correlates with a lack of E-cadherin expression in invasive breast cancer cell lines and in breast tumor specimens, supporting an in vivo role for the miR-200 family in EMT repression (118).”
MicroRNA-155 Is Regulated by the Transforming Growth Factor β/Smad Pathway and Contributes to Epithelial Cell Plasticity by Targeting RhoA (2008, background): “Recent reports have shown the importance of microRNA-200 (miR-200) family downregulation during EMT (2, 12, 21, 36); however, the functions of upregulated miRNAs during TGF- -induced EMT remain uncharacterized.”
TGF-β Signaling from Receptors to Smads (2016, positive): “proximal promoter element and repress the transcription of miR-200, and are reciprocally targeted by miR-200 (Burk et al. 2008; Korpal et al. 2008).”
Involvement of members of the cadherin superfamily in cancer. (2009, background): “…family and miR-205 directly target ZEB1/deltaEF1 and ZEB2/SIP1 mRNAs, thereby repressing ZEB1 and ZEB2 protein translation and hence increasing E-cadherin expression (Christoffersen et al. 2007; Hurteau et al. 2007; Burk et al. 2008; Gregory et al. 2008; Korpal et al. 2008; Park et al. 2008).”
TGF-β/Smad signaling in renal fibrosis (2015, background): “As miR200 has a major role in maintaining the epithelial differentiation, delivery of miR-200b significantly reduces renal fibrotic response by suppressing the transcriptional repressors of E-cadherin ZEB1 and ZEB2 (Korpal et al., 2008; Oba et al., 2010).”
Epithelial-mesenchymal transitions: insights from development (2012, background): “Peinado et al., 2007 Twist Contains a basic helix-loop-helix motif that interacts with Bmi1, together with the PRC2 complex to repress E-cadherin and p16INK4a through chromatin remodeling.”
Epithelial-mesenchymal plasticity in cancer progression and metastasis (2019, background): “The miR-200 family of five miRNAs and miR-205 repress the expression of Zeb1/2 (Bracken et al., 2008; Burk et al., 2008; Gregory et al., 2008; Korpal et al., 2008; Park et al., 2008). miR-200s and Zeb1/2 form a double negative feedback loop where ZEB1/2 inhibits the expression of miR-200 miRNAs, and”