Knoll, Susanne, Fürst, Katharina, Kowtharapu, Bhavani, Schmitz, Ulf, Marquardt, Stephan, Wolkenhauer, Olaf, Martin, Hubert, and Pützer, Brigitte (2014) E2F1 induces miR-224/452 expression to drive EMT through TXNIP downregulation. EMBO Reports, 15. pp. 1315-1329.

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Abstract

Malignant melanoma is highly lethal due to its aggressive invasive properties and metastatic dissemination. The transcription factor E2F1 is crucial for melanoma progression through poorly understood mechanisms. Here, we show that the miR‐224/miR‐452 cluster is significantly increased in advanced melanoma and invasive/metastatic cell lines that express high levels of E2F1. miR‐224/miR‐452 expression is directly activated by E2F1 through transactivation of the GABRE gene. Ectopic expression of miR‐224/miR‐452 in less aggressive cells induces EMT and cytoskeletal rearrangements and enhances migration/invasion. Conversely, miR‐224/miR‐452 depletion in metastatic cells induces the reversal of EMT, inhibition of motility, loss of the invasive phenotype and an absence of lung metastases in mice. We identify the metastasis suppressor TXNIP as new target of miR‐224/miR‐452 that induces feedback inhibition of E2F1 and show that miR‐224/452‐mediated downregulation of TXNIP is essential for E2F1‐induced EMT and invasion. The E2F1‐miR‐224/452‐TXNIP axis constitutes a molecular signature that predicts patient survival and may help to set novel therapies.

Item ID:	69002
Item Type:	Article (Research - C1)
ISSN:	1469-3178
Copyright Information:	© 2014 The Authors
Date Deposited:	17 Jul 2024 00:11
FoR Codes:	31 BIOLOGICAL SCIENCES > 3101 Biochemistry and cell biology > 310102 Cell development, proliferation and death @ 33% 32 BIOMEDICAL AND CLINICAL SCIENCES > 3211 Oncology and carcinogenesis > 321101 Cancer cell biology @ 34% 31 BIOLOGICAL SCIENCES > 3102 Bioinformatics and computational biology > 310208 Translational and applied bioinformatics @ 33%
SEO Codes:	28 EXPANDING KNOWLEDGE > 2801 Expanding knowledge > 280103 Expanding knowledge in the biomedical and clinical sciences @ 100%
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