MicroRNAs 15a and 16 regulate tumor proliferation in multiple myeloma
- 25 June 2009
- journal article
- Published by American Society of Hematology in Blood
- Vol. 113 (26), 6669-6680
- https://doi.org/10.1182/blood-2009-01-198408
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.Keywords
This publication has 53 references indexed in Scilit:
- The miR-15a–miR-16-1 cluster controls prostate cancer by targeting multiple oncogenic activitiesNature Medicine, 2008
- MicroRNAs regulate critical genes associated with multiple myeloma pathogenesisProceedings of the National Academy of Sciences of the United States of America, 2008
- Truncation in CCND1 mRNA alters miR-16-1 regulation in mantle cell lymphomaBlood, 2008
- Targeting NF-κB in Waldenstrom macroglobulinemiaBlood, 2008
- MicroRNA Expression in Cytogenetically Normal Acute Myeloid LeukemiaThe New England Journal of Medicine, 2008
- The Akt pathway regulates survival and homing in Waldenstrom macroglobulinemiaBlood, 2007
- A novel function for HSF1-induced mitotic exit failure and genomic instability through direct interaction between HSF1 and Cdc20Oncogene, 2007
- Promiscuous Mutations Activate the Noncanonical NF-κB Pathway in Multiple MyelomaCancer Cell, 2007
- Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)–dependent migration and homing in multiple myelomaBlood, 2006
- Targeting mitochondrial factor Smac/DIABLO as therapy for multiple myeloma (MM)Blood, 2006