miR-1199-5p and Zeb1 function in a double-negative feedback loop potentially coordinating EMT and tumour metastasis

Maren Diepenbruck, Stefanie Tiede, Meera Saxena, Robert Ivanek, Ravi Kiran Reddy Kalathur, Fabiana Lüönd, Nathalie Meyer-Schaller () and Gerhard Christofori ()
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Maren Diepenbruck: University of Basel
Stefanie Tiede: University of Basel
Meera Saxena: University of Basel
Robert Ivanek: University of Basel
Ravi Kiran Reddy Kalathur: University of Basel
Fabiana Lüönd: University of Basel
Nathalie Meyer-Schaller: University of Basel
Gerhard Christofori: University of Basel

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract Epithelial tumour cells can gain invasive and metastatic capabilities by undergoing an epithelial–mesenchymal transition. Transcriptional regulators and post-transcriptional effectors like microRNAs orchestrate this process of high cellular plasticity and its malignant consequences. Here, using microRNA sequencing in a time-resolved manner and functional validation, we have identified microRNAs that are critical for the regulation of an epithelial–mesenchymal transition and of mesenchymal tumour cell migration. We report that miR-1199-5p is downregulated in its expression during an epithelial–mesenchymal transition, while its forced expression prevents an epithelial–mesenchymal transition, tumour cell migration and invasion in vitro, and lung metastasis in vivo. Mechanistically, miR-1199-5p acts in a reciprocal double-negative feedback loop with the epithelial–mesenchymal transition transcription factor Zeb1. This function resembles the activities of miR-200 family members, guardians of an epithelial cell phenotype. However, miR-1199-5p and miR-200 family members share only six target genes, indicating that, besides regulating Zeb1 expression, they exert distinct functions during an epithelial–mesenchymal transition.

Date: 2017
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DOI: 10.1038/s41467-017-01197-w

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