A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells

By U. Burk, Jörg Schubert, U. Wellner, O. Schmalhofer, E. Vincan, S. Spaderna, Thomas Brabletz. EMBO Reports, 2008

1,811 citations recorded by the source corpus.

The embryonic programme ‘epithelial–mesenchymal transition’ (EMT) is thought to promote malignant tumour progression. The transcriptional repressor zinc‐finger E‐box binding homeobox 1 (ZEB1) is a crucial inducer of EMT in various human tumours, and was recently shown to promote invasion and metastasis of tumour cells. Here, we report that ZEB1 directly suppresses transcription of microRNA‐200 family members miR‐141 and miR‐200c, which strongly activate epithelial differentiation in pancreatic, colorectal and breast cancer cells. Notably, the EMT activators transforming growth factor β2 and ZEB1 are the predominant targets downregulated by these microRNAs. These results indicate that ZEB1 triggers an microRNA‐mediated feedforward loop that stabilizes EMT and promotes invasion of cancer cells. Alternatively, depending on the environmental trigger, this loop might switch and induce epithelial differentiation, and thus explain the strong intratumorous heterogeneity observed in many human cancers.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/0719bae602eb3c2d676032c7d3621df871f93c04

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Citations in the corpus

Overview of MicroRNA Biology (2015, background): “27 However, if miR-200c is overexpressed it targets ZEB1 allowing for transcription, creating a forward-feedback loop.”
ISMARA: automated modeling of genomic signals as a democracy of regulatory motifs (2014, background): “Tiwari N, Meyer-Schaller N, Arnold P, Antoniadis H, Pachkov M, van Nimwegen E, Christofori G. 2013a. Klf4 is a transcriptional regulator of genes critical for EMT, including Jnk1 (Mapk8).”
A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition. (2008, background): “Furthermore, the miR200cf141 promoter has a conserved pair of E-boxes near the TSS and is similarly subject to repression by ZEB1 (24).”
E-cadherin, β-catenin, and ZEB1 in malignant progression of cancer (2009, background): “As both miRNAs affect the expression of molecules acting in a proinvasive manner, such as cofilin, the leptin receptor, TGFβ2 and, in particular, ZEB1, this suggests an EMT-enhancing feed forward loop in invading cancer cells [131, 132, 135, 161, 205].”
Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization (2011, background): “Notably, miR-200s have recently been shown to inhibit EMT and promote MET by direct targeting of E-cadherin transcriptional repressors Zeb1 and Zeb2 (refs”
MicroRNA function in cancer: oncogene or a tumor suppressor? (2009, background): “Furthermore, miR-141 and miR-200c, members of the miRNA-200 family, act as oncogenes by targeting and down-regulating zincfinger E-box binding homeobox 1 (ZEB1), a crucial inducer of epithelial-mesenchymal transition in various human tumors [37].”
Involvement of members of the cadherin superfamily in cancer. (2009, background): “Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a003129 in the promoter regions of polycistronic primary miRNAs encoding these miRNAs (Bracken et al. 2008; Burk et al. 2008).”
Epithelial-Mesenchymal Plasticity: A central regulator of cancer progression (2015, background): “…of the Zeb family form a double-negative feedback loop with the miR-200 family of microRNAs, causing this regulatory loop to operate as a bi-stable switch between the epithelial and mesenchymal state in a variety of carcinomas (Brabletz and Brabletz, 2010; Burk et al., 2008; Hill et al., 2013).”
MicroRNAs in development and disease. (2011, background): “This finding is common to many other cancer forms (2, 63, 215, 310, 313, 472) and is consistent with the fact that the milder form of RCC is not associated with downregulation of the miR-200 family (440).”
EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer (2010, background): “Most significantly, EMT is regulated by the expression of the mir-200 family and mir-205 (Burk et al., 2008; Gregory et al., 2008; Korpal et al., 2008; Park et al., 2008).”
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).”