Priority Research Papers:

Contact inhibition modulates intracellular levels of miR-223 in a p27kip1-dependent manner

Joshua Armenia, Linda Fabris, Francesca Lovat, Stefania Berton, Ilenia Segatto, Sara D’Andrea, Cristina Ivan, Luciano Cascione, George A. Calin, Carlo M. Croce, Alfonso Colombatti, Andrea Vecchione, Barbara Belletti and Gustavo Baldassarre _

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Oncotarget. 2014; 5:1185-1197. https://doi.org/10.18632/oncotarget.1803

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Joshua Armenia1, Linda Fabris1, Francesca Lovat2, Stefania Berton1, Ilenia Segatto1, Sara D’Andrea1, Cristina Ivan3, Luciano Cascione2, George A. Calin3, Carlo M. Croce2, Alfonso Colombatti1,4, Andrea Vecchione2,5, Barbara Belletti1 and Gustavo Baldassarre1

1 Division of Experimental Oncology 2, CRO, National Cancer Institute, Aviano, Italy.

2 Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA.

3 Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, TX

4 Department of Biomedical Sciences and Technologies, MATI Center of Excellence, University of Udine, Udine, Italy.

5 Division of Pathology, II University of Rome “La Sapienza”, Santo Andrea Hospital, Rome, Italy.


Gustavo Baldassarre, email:

Barbara Belletti, email:

Keywords: p27kip1, miR-223, RNA binding, contact inhibition

Received: February 18, 2014 Accepted: March 2, 2014 Published: March 4, 2014


MicroRNAs (miRs) are a large class of small regulatory RNAs that function as nodes of signaling networks. This implicates that miRs expression has to be finely tuned, as observed during cell cycle progression.

Here, using an expression profiling approach, we provide evidence that the CDK inhibitor p27Kip1 regulates miRs expression following cell cycle exit. By using wild type and p27KO cells harvested in different phases of the cell cycle we identified several miRs regulated by p27Kip1 during the G1 to S phase transition. Among these miRs, we identified miR-223 as a miR specifically upregulated by p27Kip1 in G1 arrested cells. Our data demonstrate that p27Kip1 regulated the expression of miR-223, via two distinct mechanisms. p27Kip1 directly stabilized mature miR-223 expression, acting as a RNA binding protein and it controlled E2F1 expression that, in turn, regulated miR-223 promoter activity. The resulting elevated miR-223 levels ultimately participated to arresting cell cycle progression following contact inhibition. Importantly, this mechanism of growth control was conserved in human cells and deranged in breast cancers.

Here, we identify a novel and conserved function of p27Kip1 that, by modulating miR-223 expression, contributes to proper regulation of cell cycle exit following contact inhibition. Thus we propose a new role for miR-223 in the regulation of breast cancer progression.

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