1. ¹Institute of Genetics and Biophysics A. Buzzati Traverso, CNR, Naples, Italy
2. ²Department of Biochemistry and Biophysics, Second University of Naples Medical School, Naples, Italy
3. ³Department of Molecular and Cellular Biology and Pathology, Federico II University of Naples Medical School, Naples, Italy

Correspondence: Dr P Verde, Institute of Genetics and Biophysics 'A Buzzati Traverso', Inst. Genetics & Biophysics, CNR, via P. Castellino 111, Naples, Naples, 80131, Italy. E-mail: verde@igb.cnr.it

Received 14 April 2008; Revised 15 August 2008; Accepted 29 August 2008; Published online 13 October 2008.

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.