MicroRNAs regulate critical genes associated with multiple myeloma pathogenesis.

Abstract

Progress in understanding the biology of multiple myeloma (MM), a plasma cell malignancy, has been slow. The discovery of microRNAs (miRNAs), a class of small noncoding RNAs targeting multiple mRNAs, has revealed a new level of gene expression regulation. To determine whether miRNAs play a role in the malignant transformation of plasma cells (PCs), we have used both miRNA microarrays and quantitative real time PCR to profile miRNA expression in MM-derived cell lines (n = 49) and CD138+ bone marrow PCs from subjects with MM (n = 16), monoclonal gammopathy of undetermined significance (MGUS) (n = 6), and normal donors (n = 6). We identified overexpression of miR-21, miR-106b approximately 25 cluster, miR-181a and b in MM and MGUS samples with respect to healthy PCs. Selective up-regulation of miR-32 and miR-17 approximately 92 cluster was identified in MM subjects and cell lines but not in MGUS subjects or healthy PCs. Furthermore, two miRNAs, miR-19a and 19b, that are part of the miR-17 approximately 92 cluster, were shown to down regulate expression of SOCS-1, a gene frequently silenced in MM that plays a critical role as inhibitor of IL-6 growth signaling. We also identified p300-CBP-associated factor, a gene involved in p53 regulation, as a bona fide target of the miR106b approximately 25 cluster, miR-181a and b, and miR-32. Xenograft studies using human MM cell lines treated with miR-19a and b, and miR-181a and b antagonists resulted in significant suppression of tumor growth in nude mice. In summary, we have described a MM miRNA signature, which includes miRNAs that modulate the expression of proteins critical to myeloma pathogenesis.

• Authors: Flavia Pichiorri, Sung-Suk Suh, Marco Ladetto, Michael Kuehl, Tiziana Palumbo, Daniela Drandi, Cristian Taccioli, Nicola Zanesi, Hansjuerg Alder, John P Hagan, Reinhold Munker, Stefano Volinia, Mario Boccadoro, Ramiro Garzon, Antonio Palumbo, Rami I Aqeilan, Carlo M Croce
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 105 Issue 35 Pg. 12885-90 (Sep 02 2008) ISSN: 1091-6490 [Electronic] United States
• PMID: 18728182 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• BCL2L11 protein, human
• Bcl-2-Like Protein 11
• Bcl2l11 protein, mouse
• Membrane Proteins
• MicroRNAs
• Proto-Oncogene Proteins
• Receptors, Interleukin-6
• Repressor Proteins
• SOCS1 protein, human
• STAT3 Transcription Factor
• Suppressor of Cytokine Signaling 1 Protein
• Suppressor of Cytokine Signaling Proteins
• Tumor Suppressor Protein p53
• p300-CBP Transcription Factors
• p300-CBP-associated factor

Topics

• Animals
• Apoptosis Regulatory Proteins (metabolism)
• Base Sequence
• Bcl-2-Like Protein 11
• Cell Line, Tumor
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Genes, Neoplasm
• Health
• Humans
• Membrane Proteins (metabolism)
• Mice
• Mice, Nude
• MicroRNAs (genetics, metabolism)
• Molecular Sequence Data
• Monoclonal Gammopathy of Undetermined Significance
• Multiple Myeloma (genetics, pathology)
• Plasma Cells (metabolism, pathology)
• Proto-Oncogene Proteins (metabolism)
• Receptors, Interleukin-6 (metabolism)
• Repressor Proteins (metabolism)
• Reproducibility of Results
• Reverse Transcriptase Polymerase Chain Reaction
• STAT3 Transcription Factor (metabolism)
• Suppressor of Cytokine Signaling 1 Protein
• Suppressor of Cytokine Signaling Proteins (metabolism)
• Tumor Suppressor Protein p53 (metabolism)
• Up-Regulation
• p300-CBP Transcription Factors (metabolism)