Home LiteratureArticle Details
PMID: 19401561 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

MicroRNAs 15a and 16 regulate tumor proliferation in multiple myeloma.

Blood ·Vol. 113 ·No. 26 ·2009-06-25 ·Pages 6669-80

Roccaro AM, Sacco A, Thompson B, Leleu X, Azab AK, Azab F, Runnels J, Jia X, Ngo HT, Melhem MR, Lin CP, Ribatti D, Rollins BJ, Witzig TE, Anderson KC, Ghobrial IM

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.

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,genetics,physiology Mitogen-Activated Protein Kinases/antagonists & inhibitors,metabolism Multiple Myeloma/genetics,metabolism,pathology NF-kappa B/antagonists & inhibitors,metabolism Neoplasm Proteins/antagonists & inhibitors,metabolism Neoplastic Stem Cells/cytology,metabolism Prognosis Protein Kinase Inhibitors/pharmacology Proto-Oncogene Proteins c-akt/antagonists & inhibitors,metabolism RNA, Neoplasm/biosynthesis,genetics,physiology Ribosomal Protein S6/antagonists & inhibitors,metabolism Stromal Cells/cytology
Chemicals
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
Authors & Affiliations
16 authors, click to expand affiliations / ORCID
Roccaro Aldo M
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.
Sacco Antonio
Thompson Brian
Leleu Xavier
Azab Abdel Kareem
Azab Feda
Runnels Judith
Jia Xiaoying
Ngo Hai T
Melhem Molly R
Lin Charles P
Ribatti Domenico
Rollins Barrett J
Witzig Thomas E
Anderson Kenneth C
Ghobrial Irene M
References (53)
53 references, click to expand
  1. Combinatorial microRNA target predictions.
    Nat Genet. 2005 May;37(5):495-500 PMID: 15806104
  2. A phase 2 study of bortezomib in relapsed, refractory myeloma.
    N Engl J Med. 2003 Jun 26;348(26):2609-17 PMID: 12826635
  3. Multiple myeloma.
    N Engl J Med. 2004 Oct 28;351(18):1860-73 PMID: 15509819
  4. Identification of hundreds of conserved and nonconserved human microRNAs.
    Nat Genet. 2005 Jul;37(7):766-70 PMID: 15965474
  5. Cancer statistics, 2005.
    CA Cancer J Clin. 2005 Jan-Feb;55(1):10-30 PMID: 15661684
  6. Myeloma and the t(11;14)(q13;q32); evidence for a biologically defined unique subset of patients.
    Blood. 2002 May 15;99(10):3735-41 PMID: 11986230
  7. Genetics and cytogenetics of multiple myeloma: a workshop report.
    Cancer Res. 2004 Feb 15;64(4):1546-58 PMID: 14989251
  8. Bortezomib mediates antiangiogenesis in multiple myeloma via direct and indirect effects on endothelial cells.
    Cancer Res. 2006 Jan 1;66(1):184-91 PMID: 16397231
  9. The small-molecule VEGF receptor inhibitor pazopanib (GW786034B) targets both tumor and endothelial cells in multiple myeloma.
    Proc Natl Acad Sci U S A. 2006 Dec 19;103(51):19478-83 PMID: 17164332
  10. A novel function for HSF1-induced mitotic exit failure and genomic instability through direct interaction between HSF1 and Cdc20.
    Oncogene. 2008 May 8;27(21):2999-3009 PMID: 18059335
  11. miR-15 and miR-16 induce apoptosis by targeting BCL2.
    Proc Natl Acad Sci U S A. 2005 Sep 27;102(39):13944-9 PMID: 16166262
  12. A paracrine loop in the vascular endothelial growth factor pathway triggers tumor angiogenesis and growth in multiple myeloma.
    Haematologica. 2003 Feb;88(2):176-85 PMID: 12604407
  13. Embelin, an inhibitor of X chromosome-linked inhibitor-of-apoptosis protein, blocks nuclear factor-kappaB (NF-kappaB) signaling pathway leading to suppression of NF-kappaB-regulated antiapoptotic and metastatic gene products.
    Mol Pharmacol. 2007 Jan;71(1):209-19 PMID: 17028156
  14. MicroRNA gene expression deregulation in human breast cancer.
    Cancer Res. 2005 Aug 15;65(16):7065-70 PMID: 16103053
  15. TAB2 and TAB3 activate the NF-kappaB pathway through binding to polyubiquitin chains.
    Mol Cell. 2004 Aug 27;15(4):535-48 PMID: 15327770
  16. Role of the TAB2-related protein TAB3 in IL-1 and TNF signaling.
    EMBO J. 2003 Dec 1;22(23):6277-88 PMID: 14633987
  17. International staging system for multiple myeloma.
    J Clin Oncol. 2005 May 20;23(15):3412-20 PMID: 15809451
  18. Targeting mitochondrial factor Smac/DIABLO as therapy for multiple myeloma (MM).
    Blood. 2007 Feb 1;109(3):1220-7 PMID: 17032924
  19. MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias.
    Proc Natl Acad Sci U S A. 2004 Aug 10;101(32):11755-60 PMID: 15284443
  20. Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma.
    Cancer Cell. 2007 Aug;12(2):131-44 PMID: 17692805
  21. Akt/PKB signaling in cancer: a function in cell motility and invasion.
    Cell Cycle. 2006 Mar;5(6):603-5 PMID: 16582622
  22. Targeting Akt3 signaling in malignant melanoma using isoselenocyanates.
    Clin Cancer Res. 2009 Mar 1;15(5):1674-85 PMID: 19208796
  23. A VEGF-dependent autocrine loop mediates proliferation and capillarogenesis in bone marrow endothelial cells of patients with multiple myeloma.
    Thromb Haemost. 2004 Dec;92(6):1438-45 PMID: 15583754
  24. In vivo imaging of specialized bone marrow endothelial microdomains for tumour engraftment.
    Nature. 2005 Jun 16;435(7044):969-73 PMID: 15959517
  25. microRNA expression in the biology, prognosis, and therapy of Waldenström macroglobulinemia.
    Blood. 2009 Apr 30;113(18):4391-402 PMID: 19074725
  26. Adherence of multiple myeloma cells to bone marrow stromal cells upregulates vascular endothelial growth factor secretion: therapeutic applications.
    Leukemia. 2001 Dec;15(12):1950-61 PMID: 11753617
  27. The role of the bone microenvironment in the pathophysiology and therapeutic management of multiple myeloma: interplay of growth factors, their receptors and stromal interactions.
    Eur J Cancer. 2006 Jul;42(11):1564-73 PMID: 16765041
  28. The Akt pathway regulates survival and homing in Waldenstrom macroglobulinemia.
    Blood. 2007 Dec 15;110(13):4417-26 PMID: 17761832
  29. Reciprocal actions of REST and a microRNA promote neuronal identity.
    Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2422-7 PMID: 16461918
  30. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14.
    Cell. 1993 Dec 3;75(5):843-54 PMID: 8252621
  31. Multiple myeloma: evolving genetic events and host interactions.
    Nat Rev Cancer. 2002 Mar;2(3):175-87 PMID: 11990854
  32. Molecular sequelae of proteasome inhibition in human multiple myeloma cells.
    Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14374-9 PMID: 12391322
  33. MicroRNAs regulate critical genes associated with multiple myeloma pathogenesis.
    Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):12885-90 PMID: 18728182
  34. Mutations of the tumor suppressor gene SOCS-1 in classical Hodgkin lymphoma are frequent and associated with nuclear phospho-STAT5 accumulation.
    Oncogene. 2006 Apr 27;25(18):2679-84 PMID: 16532038
  35. Targeting NF-kappaB in Waldenstrom macroglobulinemia.
    Blood. 2008 May 15;111(10):5068-77 PMID: 18334673
  36. Real-time quantification of microRNAs by stem-loop RT-PCR.
    Nucleic Acids Res. 2005 Nov 27;33(20):e179 PMID: 16314309
  37. Truncation in CCND1 mRNA alters miR-16-1 regulation in mantle cell lymphoma.
    Blood. 2008 Aug 1;112(3):822-9 PMID: 18483394
  38. Deregulated Akt3 activity promotes development of malignant melanoma.
    Cancer Res. 2004 Oct 1;64(19):7002-10 PMID: 15466193
  39. Human let-7a miRNA blocks protein production on actively translating polyribosomes.
    Nat Struct Mol Biol. 2006 Dec;13(12):1108-14 PMID: 17128272
  40. MicroRNAs: small RNAs with a big role in gene regulation.
    Nat Rev Genet. 2004 Jul;5(7):522-31 PMID: 15211354
  41. Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia.
    Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15524-9 PMID: 12434020
  42. Prediction of mammalian microRNA targets.
    Cell. 2003 Dec 26;115(7):787-98 PMID: 14697198
  43. Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)-dependent migration and homing in multiple myeloma.
    Blood. 2007 Apr 1;109(7):2708-17 PMID: 17119115
  44. Clinical and biologic implications of recurrent genomic aberrations in myeloma.
    Blood. 2003 Jun 1;101(11):4569-75 PMID: 12576322
  45. NF-kappa B as a therapeutic target in multiple myeloma.
    J Biol Chem. 2002 May 10;277(19):16639-47 PMID: 11872748
  46. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.
    Methods. 2001 Dec;25(4):402-8 PMID: 11846609
  47. The miR-15a-miR-16-1 cluster controls prostate cancer by targeting multiple oncogenic activities.
    Nat Med. 2008 Nov;14(11):1271-7 PMID: 18931683
  48. MicroRNAs 221 and 222 inhibit normal erythropoiesis and erythroleukemic cell growth via kit receptor down-modulation.
    Proc Natl Acad Sci U S A. 2005 Dec 13;102(50):18081-6 PMID: 16330772
  49. MicroRNA expression in cytogenetically normal acute myeloid leukemia.
    N Engl J Med. 2008 May 1;358(18):1919-28 PMID: 18450603
  50. Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma.
    Cancer Cell. 2007 Aug;12(2):115-30 PMID: 17692804
  51. Systematic discovery of regulatory motifs in human promoters and 3' UTRs by comparison of several mammals.
    Nature. 2005 Mar 17;434(7031):338-45 PMID: 15735639
  52. Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341.
    Blood. 2003 Feb 15;101(4):1530-4 PMID: 12393500
  53. Identification of a human NF-kappaB-activating protein, TAB3.
    Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):2028-33 PMID: 14766965
Article Info
Journal
Blood
Abbr.
Blood
ISSN
1528-0020
DOI
10.1182/blood-2009-01-198408
Published
2009-06-25
Epub
2009-00-28
Pages
6669-80
Language
English
Region
United States
NLM ID
7603509
PMCID
PMC2710922
Subset
IM
Grants
NCI NIH HHS · R01 CA125690 · United States
NCI NIH HHS · R01 CA125690-01 · United States
External Links
PubMed source DOI: 10.1182/blood-2009-01-198408 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2