Abstract
BackgroundMiR-221 and miR-222 are two highly homologous microRNAs whose upregulation has been recently described in several types of human tumors, for some of which their oncogenic role was explained by the discovery of their target p27, a key cell cycle regulator. We previously showed this regulatory relationship in prostate carcinoma cell lines in vitro, underlying the role of miR-221/222 as inducers of proliferation and tumorigenicity.Methodology/Principal FindingsHere we describe a number of in vivo approaches confirming our previous data. The ectopic overexpression of miR-221 is able, per se, to confer a high growth advantage to LNCaP-derived tumors in SCID mice. Consistently, the anti-miR-221/222 antagomir treatment of established subcutaneous tumors derived from the highly aggressive PC3 cell line, naturally expressing high levels of miR-221/222, reduces tumor growth by increasing intratumoral p27 amount; this effect is long lasting, as it is detectable as long as 25 days after the treatment. Furthermore, we provide evidence in favour of a clinical relevance of the role of miR-221/222 in prostate carcinoma, by showing their general upregulation in patient-derived primary cell lines, where we find a significant inverse correlation with p27 expression.Conclusions/SignificanceThese findings suggest that modulating miR-221/222 levels may have a therapeutic potential in prostate carcinoma.
Highlights
MicroRNAs are short (,22 nt) RNA molecules whose relevance as regulators of gene expression has been shown in relatively recent times [1], during which, a huge amount of data have been collected demonstrating that they play extremely important roles in almost all aspects of biology, such as development and disease
We have recently shown that miR-221 and miR-222 are positive regulators of in vitro prostate carcinoma growth through the repression of p27 [9]
In order to investigate if this role is relevant in in vivo models of prostate carcinoma, we employed LNCaP cells permanently transfected with p-221 [9], expressing one of these microRNAs, miR-221 (Fig. 1A), to establish subcutaneous tumors in SCID mice, and measured tumor growth and significant features
Summary
MicroRNAs are short (,22 nt) RNA molecules whose relevance as regulators of gene expression has been shown in relatively recent times [1], during which, a huge amount of data have been collected demonstrating that they play extremely important roles in almost all aspects of biology, such as development and disease They commonly act as negative regulators of the expression of protein coding genes, usually recognizing and binding to specific sites in the 39UTRs of their mRNAs, and impairing their translation, or sometimes even inducing the degradation of the target mRNA We previously showed this regulatory relationship in prostate carcinoma cell lines in vitro, underlying the role of miR-221/222 as inducers of proliferation and tumorigenicity
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