MicroRNAs (miR)-221 and miR-222, both overexpressed in human thyroid papillary carcinomas, regulate p27Kip1 protein levels and cell cycle.
We have recently reported that MicroRNAs (miR)-221 and miR-222 were up-regulated in human thyroid papillary carcinomas in comparison with the normal thyroid tissue. Bioinformatic analysis proposed the p27(Kip1) protein, a key regulator of cell cycle, as a candidate target for the miR-221/222 cluster. Here, we report that the enforced expression of miR-221 and miR-222 was able to reduce p27(Kip1) protein levels in thyroid carcinoma and HeLa cells in the absence of significant changes in specific p27(Kip1) mRNA levels. This effect is direct as miR-221 and miR-222 negatively regulate the expression of the 3'-untranslated region-based reporter construct from the p27(Kip1) gene, and is dependent on two target sites in this region. Consistent with these results, an enforced expression of the miR-221 and miR-222 induced the thyroid papillary carcinoma cell line (TPC-1) to progress to the S phase of the cell cycle. It is likely that the negative regulation of p27(Kip1) by miR-221 and miR-222 might also have a role in vivo since we report an inverse correlation between miR-221 and miR-222 up-regulation and down-regulation of the p27(Kip1) protein levels in human thyroid papillary carcinomas. Therefore, the data reported here demonstrate that miR-221 and miR-222 are endogenous regulators of p27(Kip1) protein expression, and thereby, the cell cycle.
Visone
Rosa
R
Dipartimento di Biologia e Patologia Cellulare e Molecolare c/o Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, Facoltà di Medicina e Chirurgia, Università degli Studi di Napoli Federico II, via Pansini, 5, 80131 Naples, Italy.
Russo
Lucia
L
Pallante
Pierlorenzo
P
De Martino
Ivana
I
Ferraro
Angelo
A
Leone
Vincenza
V
Borbone
Eleonora
E
Petrocca
Fabio
F
Alder
Hansjuerg
H
Croce
Carlo Maria
CM
Fusco
Alfredo
A
D001483:Base Sequence; D002291:Carcinoma, Papillary / Q000235:genetics*; D002453:Cell Cycle / Q000235:genetics*; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics* / Q000502:physiology*; D013964:Thyroid Neoplasms / Q000235:genetics*; D014407:Tumor Cells, Cultured
D050760:Cyclin-Dependent Kinase Inhibitor p27; D047908:Intracellular Signaling Peptides and Proteins; D035683:MicroRNAs; C436291:CDKN1B protein, human; C525709:MIR221, human; C525710:MIR222, human