MicroRNAs 15a and 16 regulate tumor proliferation in multiple myeloma

Blood - Tập 113 Số 26 - Trang 6669-6680 - 2009
Aldo M. Roccaro1,2,3, Antonio Sacco4, Brian Thompson5, Xavier Leleu4, Abdel Kareem Azab4, Feda Azab4, Judith Runnels4, Xiaoying Jia4, Hai T. Ngo4, Molly Melhem4, Charles P. Lin5, Doménico Ribatti6, Barrett J. Rollins4, Thomas E. Witzig7, Kenneth C. Anderson4, Irene M. Ghobrial4
1Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy
2Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA;
3Unit of Blood Diseases and Cell Therapies, University of Brescia Medical School, Brescia, Italy;
4Department of Medical Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA;
5Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston
6Department of Human Anatomy and Histology, University of Bari Medical School, Bari, Italy; and
7Department of Hematology, Mayo Clinic, Rochester, MN

Tóm tắt

Abstract 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-κB-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.

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Blood

Tập 113 Số 26

6669-6680

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