MicroRNAs regulate critical genes associated with multiple myeloma pathogenesis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 105; no. 35; pp. 12885 - 12890
• Main Authors: Pichiorri, Flavia, Suh, Sung-Suk, Ladetto, Marco, Kuehl, Michael, Palumbo, Tiziana, Drandi, Daniela, Taccioli, Cristian, Zanesi, Nicola, Alder, Hansjuerg, Hagan, John P, Munker, Reinhold, Volinia, Stefano, Boccadoro, Mario, Garzon, Ramiro, Palumbo, Antonio, Aqeilan, Rami I, Croce, Carlo M
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 02.09.2008; National Acad Sciences
• Subjects: Animals; antagonists; Apoptosis Regulatory Proteins - metabolism; Base Sequence; Bcl-2-Like Protein 11; Biological Sciences; Bone marrow; Cell growth; Cell Line, Tumor; Cell lines; Cells; Gene expression; Gene Expression Profiling; gene expression regulation; Gene Expression Regulation, Neoplastic; genes; Genes, Neoplasm; Health; Humans; interleukin-6; Membrane Proteins - metabolism; messenger RNA; Mice; Mice, Nude; microarray technology; MicroRNA; MicroRNAs - genetics; MicroRNAs - metabolism; Molecular Sequence Data; Monoclonal Gammopathy of Undetermined Significance; Multiple myeloma; Multiple Myeloma - genetics; Multiple Myeloma - pathology; myeloma; non-coding RNA; Oligonucleotides; p300-CBP Transcription Factors - metabolism; pathogenesis; Pathology; Plasma cells; Plasma Cells - metabolism; Plasma Cells - pathology; proteins; Proto-Oncogene Proteins - metabolism; quantitative polymerase chain reaction; Receptors, Interleukin-6 - metabolism; Repressor Proteins - metabolism; Reproducibility of Results; Reverse Transcriptase Polymerase Chain Reaction; Ribonucleic acid; RNA; Rodents; Signatures; STAT3 Transcription Factor - metabolism; Studies; Suppressor of Cytokine Signaling 1 Protein; Suppressor of Cytokine Signaling Proteins - metabolism; Transfection; Tumor cell line; Tumor Suppressor Protein p53 - metabolism; Tumors; Up-Regulation
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.0806202105

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~25 cluster, miR-181a and b in MM and MGUS samples with respect to healthy PCs. Selective up-regulation of miR-32 and miR-17~92 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-17~92 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~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.