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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >MicroRNAs regulate critical genes associated with multiple myeloma pathogenesis
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MicroRNAs regulate critical genes associated with multiple myeloma pathogenesis

机译：MicroRNA调节与多发性骨髓瘤发病相关的关键基因

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摘要

Progress in understanding the biology of multiple myeloma (MM), a plasma cell malignancy, has been slow. The discovery of microR-NAs (mrRNAs), 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.
机译：在了解多发性骨髓瘤（MM）（浆细胞恶性肿瘤）的生物学研究方面进展缓慢。 microR-NA（mrRNA）是一类针对多种mRNA的小型非编码RNA，它的发现揭示了基因表达调控的新水平。为了确定miRNA在浆细胞（PC）的恶性转化中是否起作用，我们使用了miRNA微阵列和定量实时PCR来分析MM衍生的细胞系（n = 49）和CD138 +骨髓PCs中miRNA的表达。 MM（n = 16），意义不明的单克隆丙种球蛋白病（MGUS）（n = 6）和正常捐献者（n = 6）。我们在健康人的MM和MGUS样品中鉴定了miR-21，miR-106b〜25簇，miR-181a和b的过表达。在MM受试者和细胞系中发现了miR-32和miR-17〜92簇的选择性上调，而在MGUS受试者或健康的PC中则没有。此外，还显示了miR-17〜92簇中的两个miRNA miR-19a和19b会下调SOCS-1的表达，SOCS-1是MM中常沉默的基因，在IL-抑制剂中起关键作用。 6生长信号。我们还确定了与p300调控相关的基因p300-CBP相关因子是miR106b〜25簇，miR-181a和b以及miR-32的真正靶标。使用经过miR-19a和b以及miR-181a和b拮抗剂处理的人MM细胞系进行异种移植研究可显着抑制裸鼠体内肿瘤的生长。总之，我们已经描述了MM miRNA签名，其中包括可调节对骨髓瘤发病机理至关重要的蛋白质表达的miRNA。

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