E2F1 induces miR-224/452 expression to drive EMT through TXNIP downregulation.

EMBO Rep. 2014 Dec;15(12):1315-29.

Knoll S, Fürst K, Kowtharapu B, Schmitz U, Marquardt S, Wolkenhauer O, Martin H, Pützer BM.

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.

Pubmed

Vorheriger Beitrag

Emerging from the shade of p53 mutants: N-terminally truncated variants of the p53 family in EMT signaling and cancer progression.

Nächster Beitrag

A balancing act: orchestrating amino-truncated and full-length p73 variants as decisive factors in cancer progression.

E2F1 induces miR-224/452 expression to drive EMT through TXNIP downregulation.

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