miR-221 and miR-222 Expression Affects the Proliferation Potential of Human Prostate Carcinoma Cell Lines by Targeting p27Kip1*

By Silvia Galardi, N. Mercatelli, E. Giorda, Simone Massalini, G. Frajese, S. Ciafrè, M. Farace. Journal of Biological Chemistry, 2007

782 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/409546ae838507f1bcb737921a014b2fbe14393b

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Citations in the corpus

MicroRNA and cancer (2012, background): “This may be of particular importance in glioblastomas and prostate cancers where p27 expression shows an inverse correlation to miR221 and miR222 levels (Galardi et al., 2007; Gillies and Lorimer, 2007; le Sage et al., 2007).”
MicroRNA signature predicts survival and relapse in lung cancer. (2008, background): “the acceleration of cell cycle in prostate cancer cells (Galardi et al., 2007).”
Diagnostic and prognostic implications of microRNA profiling in prostate carcinoma (2009, background): “Hsa-miR-221 and hsa-miR-222 expression negatively correlated with p27 expression in PC3 cells derived tumor xenografts(45) and their upregulation promoted growth of LNCaP cells.(46) However, the role of these 2 miRNAs is still contradictory as their downregulation was frequently observed in prostate”
MicroRNAs in development and disease. (2011, background): “In contrast to miR21, miR-221 increases in androgen-independent tumors (586) and positively regulates cell proliferation, colony formation, and tumor growth through directly suppressing p27 (193, 419).”
MicroRNAs: key players in the immune system, differentiation, tumorigenesis and cell death (2008, background): “Contrary to increasing cell death, miR-221 and miR-222 were shown to directly target p27Kip1 in a prostate tumor cell line model, resulting in proliferation and increased oncogenesis (Galardi et al., 2007; Gillies and Lorimer, 2007; le Sage et al., 2007).”
Genomic profiling of microRNA and mRNA reveals deregulated microRNA expression in prostate cancer (2008, background): “The miR-221 cluster has been found to regulate the p27 tumor suppressor and may have oncogenic properties in prostate cancer (49).”