The inhibition of the highly expressed miR-221 and miR-222 impairs the growth of prostate carcinoma xenografts in mice.
BACKGROUND
MiR-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.


RESULTS
Here 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
These findings suggest that modulating miR-221/222 levels may have a therapeutic potential in prostate carcinoma.
Mercatelli
Neri
N
Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Rome, Italy.
Coppola
Valeria
V
Bonci
Desirée
D
Miele
Francesca
F
Costantini
Arianna
A
Guadagnoli
Marco
M
Bonanno
Elena
E
Muto
Giovanni
G
Frajese
Giovanni Vanni
GV
De Maria
Ruggero
R
Spagnoli
Luigi Giusto
LG
Farace
Maria Giulia
MG
Ciafrè
Silvia Anna
SA
D000368:Aged; D000818:Animals; D001483:Base Sequence; D002277:Carcinoma / Q000235:genetics / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects*; D018450:Disease Progression; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015316:Genetic Therapy; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000235:genetics; D008875:Middle Aged; D009841:Oligonucleotides / Q000494:pharmacology*; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D035683:MicroRNAs; D009841:Oligonucleotides; D018809:Proliferating Cell Nuclear Antigen; C525709:MIR221, human; C525710:MIR222, human; C477371:locked nucleic acid; C413374:p27 antigen