MicroRNAs 15a and 16 regulate tumor proliferation in multiple myeloma.
Detailed genomic studies have shown that cytogenetic abnormalities contribute to multiple myeloma (MM) pathogenesis and disease progression. Nevertheless, little is known about the characteristics of MM at the epigenetic level and specifically how microRNAs regulate MM progression in the context of the bone marrow milieu. Therefore, we performed microRNA expression profiling of bone marrow derived CD138(+) MM cells versus their normal cellular counterparts and validated data by qRT-PCR. We identified a MM-specific microRNA signature characterized by down-expression of microRNA-15a/-16 and overexpression of microRNA-222/-221/-382/-181a/-181b (P < .01). We investigated the functional role of microRNA-15a and -16 and showed that they regulate proliferation and growth of MM cells in vitro and in vivo by inhibiting AKT serine/threonine-protein-kinase (AKT3), ribosomal-protein-S6, MAP-kinases, and NF-kappaB-activator MAP3KIP3. Moreover, miRNA-15a and -16 exerted their anti-MM activity even in the context of the bone marrow milieu in vitro and in vivo. These data indicate that microRNAs play a pivotal role in the biology of MM and represent important targets for novel therapies in MM.
Roccaro
Aldo M
AM
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.
Sacco
Antonio
A
Thompson
Brian
B
Leleu
Xavier
X
Azab
Abdel Kareem
AK
Azab
Feda
F
Runnels
Judith
J
Jia
Xiaoying
X
Ngo
Hai T
HT
Melhem
Molly R
MR
Lin
Charles P
CP
Ribatti
Domenico
D
Rollins
Barrett J
BJ
Witzig
Thomas E
TE
Anderson
Kenneth C
KC
Ghobrial
Irene M
IM
D020533:Angiogenesis Inhibitors / Q000502:physiology; D000818:Animals; D002448:Cell Adhesion; D002455:Cell Division / Q000502:physiology; D017322:Clinical Trials, Phase II as Topic / Q000706:statistics & numerical data; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000166:cytology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D038601:Ribosomal Protein S6 / Q000037:antagonists & inhibitors / Q000378:metabolism; D017154:Stromal Cells / Q000166:cytology
D020533:Angiogenesis Inhibitors; C505361:MIRN15 microRNA, human; C505362:MIRN16 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D012334:RNA, Neoplasm; D038601:Ribosomal Protein S6; C491754:AKT3 protein, human; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases