MicroRNAs 15a and 16 regulate tumor proliferation in multiple myeloma

Aldo M Roccaro; Antonio Sacco; Brian Thompson; Xavier Leleu; Abdel Kareem Azab; Feda Azab; Judith Runnels; Xiaoying Jia; Hai T Ngo; Molly R Melhem; Charles P Lin; Domenico Ribatti; Barrett J Rollins; Thomas E Witzig; Kenneth C Anderson; Irene M Ghobrial

doi:10.1182/blood-2009-01-198408

MicroRNAs 15a and 16 regulate tumor proliferation in multiple myeloma

Blood. 2009 Jun 25;113(26):6669-80. doi: 10.1182/blood-2009-01-198408. Epub 2009 Apr 28.

Authors

Aldo M Roccaro¹, Antonio Sacco, Brian Thompson, Xavier Leleu, Abdel Kareem Azab, Feda Azab, Judith Runnels, Xiaoying Jia, Hai T Ngo, Molly R Melhem, Charles P Lin, Domenico Ribatti, Barrett J Rollins, Thomas E Witzig, Kenneth C Anderson, Irene M Ghobrial

Affiliation

¹ Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.

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-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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Angiogenesis Inhibitors / physiology
Animals
Cell Adhesion
Cell Division / physiology
Clinical Trials, Phase II as Topic / statistics & numerical data
Coculture Techniques
Endothelial Cells / cytology
Gene Expression Profiling
Gene Expression Regulation, Neoplastic*
Humans
Mice
Mice, SCID
MicroRNAs / biosynthesis
MicroRNAs / genetics
MicroRNAs / physiology*
Mitogen-Activated Protein Kinases / antagonists & inhibitors
Mitogen-Activated Protein Kinases / metabolism
Multiple Myeloma / genetics
Multiple Myeloma / metabolism
Multiple Myeloma / pathology*
NF-kappa B / antagonists & inhibitors
NF-kappa B / metabolism
Neoplasm Proteins / antagonists & inhibitors
Neoplasm Proteins / metabolism
Neoplastic Stem Cells / cytology
Neoplastic Stem Cells / metabolism
Prognosis
Protein Kinase Inhibitors / pharmacology
Proto-Oncogene Proteins c-akt / antagonists & inhibitors
Proto-Oncogene Proteins c-akt / metabolism
RNA, Neoplasm / biosynthesis
RNA, Neoplasm / genetics
RNA, Neoplasm / physiology*
Ribosomal Protein S6 / antagonists & inhibitors
Ribosomal Protein S6 / metabolism
Stromal Cells / cytology

Substances

Angiogenesis Inhibitors
MIRN15 microRNA, human
MIRN16 microRNA, human
MicroRNAs
NF-kappa B
Neoplasm Proteins
Protein Kinase Inhibitors
RNA, Neoplasm
Ribosomal Protein S6
AKT3 protein, human
Proto-Oncogene Proteins c-akt
Mitogen-Activated Protein Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding