MicroRNA and proliferation control in chronic lymphocytic leukemia: functional relationship between miR-221/222 cluster and p27.
We investigated functional relationships between microRNA 221/222 (miR-221/222) cluster and p27, a key regulator of cell cycle, in chronic lymphocytic leukemia (CLL). The enforced expression of miR-221/222 in the CLL cell line MEC1 induced a significant down-regulation of p27 protein and conferred a proliferative advantage to the transduced cells that exhibited faster progression into the S phase of the cell cycle. Accordingly, expression of miR-221/miR-222 and p27 was found to be inversely related in leukemic cells obtained from peripheral blood (PB) of 38 patients with CLL. Interestingly, when miR-221/222 and p27 protein were evaluated in different anatomic compartments (lymph nodes or bone marrow) of the same patients, increased expression of the 2 miRNAs became apparent compared with PB. This finding was paralleled by a low expression of p27. In addition, when CLL cells were induced in vitro to enter cell cycle (eg, with cytosine phosphate guanine oligodeoxynucleotide), a significant increase of miR-221/222 expression and a marked down-regulation of p27 protein were evident. These data indicate that the miR-221/222 cluster modulates the expression of p27 protein in CLL cells and lead to suggest that miR-221/222 and p27 may represent a regulatory loop that helps maintaining CLL cells in a resting condition.
Frenquelli
Michela
M
Department of Oncology, Unit and Laboratory of Lymphoid Malignancies, San Raffaele Scientific Institute and Universita Vita-Salute San Raffaele, Milan, Italy.
Muzio
Marta
M
Scielzo
Cristina
C
Fazi
Claudia
C
Scarfò
Lydia
L
Rossi
Claudia
C
Ferrari
Giuliana
G
Ghia
Paolo
P
Caligaris-Cappio
Federico
F
D015153:Blotting, Western; D002453:Cell Cycle; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics*; D005455:Fluorescent Antibody Technique; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D050760:Cyclin-Dependent Kinase Inhibitor p27; D035683:MicroRNAs; D012333:RNA, Messenger; C525709:MIR221, human; C525710:MIR222, human