Journal of Biological Chemistry
Volume 282, Issue 32, 10 August 2007, Pages 23716-23724
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RNA-Mediated Regulation and Noncoding RNA
miR-221 and miR-222 Expression Affects the Proliferation Potential of Human Prostate Carcinoma Cell Lines by Targeting p27Kip1*

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MicroRNAs are short regulatory RNAs that negatively modulate protein expression at a post-transcriptional level and are deeply involved in the pathogenesis of several types of cancers. Here we show that miR-221 and miR-222, encoded in tandem on chromosome X, are overexpressed in the PC3 cellular model of aggressive prostate carcinoma, as compared with LNCaP and 22Rv1 cell line models of slowly growing carcinomas. In all cell lines tested, we show an inverse relationship between the expression of miR-221 and miR-222 and the cell cycle inhibitor p27Kip1. We recognize two target sites for the microRNAs in the 3′ untranslated region of p27 mRNA, and we show that miR-221/222 ectopic overexpression directly results in p27 down-regulation in LNCaP cells. In those cells, we demonstrate that the ectopic overexpression of miR-221/222 strongly affects their growth potential by inducing a G1 to S shift in the cell cycle and is sufficient to induce a powerful enhancement of their colony-forming potential in soft agar. Consistently, miR-221 and miR-222 knock-down through antisense LNA oligonucleotides increases p27Kip1 in PC3 cells and strongly reduces their clonogenicity in vitro. Our results suggest that miR-221/222 can be regarded as a new family of oncogenes, directly targeting the tumor suppressor p27Kip1, and that their overexpression might be one of the factors contributing to the oncogenesis and progression of prostate carcinoma through p27Kip1 down-regulation.

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*

This work was supported in part by grants from the Italian Ministry of Instruction, University and Scientific Research (MIUR) and FIRB (Fondo pep gli Investimenti della Ricerca di Base) Grant RBNE01MBEC (to M. G. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1

These authors contributed equally to this work.

2

Recipient of a Ph.D. fellowship in endocrinology, University of Rome “Tor Vergata,” granted by Astra-Zeneca Pharmaceutics, Italy.

3

Recipient of a Ph.D. fellowship in advanced technologies in bio-medicine, University of Rome “Tor Vergata.”