Regulation of the p27(Kip1) tumor suppressor by miR-221 and miR-222 promotes cancer cell proliferation.
MicroRNAs (miRNAs) are potent post-transcriptional regulators of protein coding genes. Patterns of misexpression of miRNAs in cancer suggest key functions of miRNAs in tumorigenesis. However, current bioinformatics tools do not entirely support the identification and characterization of the mode of action of such miRNAs. Here, we used a novel functional genetic approach and identified miR-221 and miR-222 (miR-221&222) as potent regulators of p27(Kip1), a cell cycle inhibitor and tumor suppressor. Using miRNA inhibitors, we demonstrate that certain cancer cell lines require high activity of miR-221&222 to maintain low p27(Kip1) levels and continuous proliferation. Interestingly, high levels of miR-221&222 appear in glioblastomas and correlate with low levels of p27(Kip1) protein. Thus, deregulated expression of miR-221&222 promotes cancerous growth by inhibiting the expression of p27(Kip1).
le Sage
Carlos
C
Division of Tumor Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Nagel
Remco
R
Egan
David A
DA
Schrier
Mariette
M
Mesman
Elly
E
Mangiola
Annunziato
A
Anile
Corrado
C
Maira
Giulio
G
Mercatelli
Neri
N
Ciafrè
Silvia Anna
SA
Farace
Maria Giulia
MG
Agami
Reuven
R
D016475:3T3 Cells; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000502:physiology*; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D009369:Neoplasms / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D035683:MicroRNAs; D050760:Cyclin-Dependent Kinase Inhibitor p27