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An autoregulatory loop mediated by miR-21 and PDCD4 controls the AP-1 activity in RAS transformation

Abstract

The transcription factor AP-1 plays key roles in tumorigenesis, by regulating a variety of protein-coding genes, implicated in multiple hallmarks of cancer. Among non-coding genes, no AP-1 target has been described yet in tumorigenesis. MicroRNAs (miRNAs) are negative post-transcriptional regulators of protein-coding genes. miRNA expression signatures are highly relevant in cancer and several tumor-associated miRNAs (oncomirs) play critical roles in oncogenesis. Here, we show that the miRNA miR-21, which represents the most frequently upregulated oncomir in solid tumors, is induced by AP-1 in response to RAS. By analyzing validated miR-21 targets, we have found that the tumor suppressors PTEN and PDCD4 are downregulated by RAS in an AP-1- and miR-21-dependent fashion. We further show that, given the role of PDCD4 as negative regulator of AP-1, the miR-21-mediated downregulation of PDCD4 is essential for the maximal induction of AP-1 activity in response to RAS. Our data reveal a novel mechanism of positive autoregulation of the AP-1 complex in RAS transformation and disclose the function of oncomirs as critical targets and regulators of AP-1 in tumorigenesis.

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Acknowledgements

We thank Robert Hennigan (University of Cincinnati, USA), Nancy Colburn (NCI, NIH, USA), Anders Lund (University of Copenhagen, Denmark) and Hideo Iba (University of Tokyo, Japan) for expression and reporter constructs. We also thank Floriana Della Ragione and Ingram Iaccarino (IGB) for technical help and critical reading of the paper. This work was supported by grants from AIRC (Associazione Italiana per la Ricerca sul Cancro) and AICR (Association for International Cancer Research, UK) to PV and AIRC and EU-Project-SIROCCO (Grant LSHG-CT-2006-037900) to RDL.

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Correspondence to P Verde.

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Talotta, F., Cimmino, A., Matarazzo, M. et al. An autoregulatory loop mediated by miR-21 and PDCD4 controls the AP-1 activity in RAS transformation. Oncogene 28, 73–84 (2009). https://doi.org/10.1038/onc.2008.370

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