MicroRNAs regulate critical genes associated with multiple myeloma pathogenesis
MicroRNAs regulate critical genes associated with multiple myeloma pathogenesis
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DOI：
10.1073/pnas.0806202105
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发表时间：
2008-09-02
影响因子：
11.1
通讯作者：
Croce, Carlo M.
中科院分区：
文献类型：
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作者：
Pichiorri, Flavia;Suh, Sung-Suk;Croce, Carlo M.
对多发性骨髓瘤（MM）（一种浆细胞恶性肿瘤）生物学的理解进展缓慢。microRNA（miRNAs）是一类靶向多个mRNA的小的非编码RNA，它的发现揭示了基因表达调控的新水平。为了确定miRNA是否在浆细胞（PC）的恶性转化中发挥作用，我们使用miRNA微阵列和定量真实的时间PCR来分析来自MM受试者（n = 16）、未确定意义的单克隆丙种球蛋白病（MGUS）受试者（n = 6）和正常供体（n = 6）的MM衍生细胞系（n = 49）和CD 138+骨髓PC中的miRNA表达。与健康PC相比，我们在MM和MGUS样本中鉴定了miR-21、miR-106 B（类似于25簇）、miR-181 a和B的过表达。在MM受试者和细胞系中发现了类似于92簇的miR-32和miR-17的选择性上调，但在MGUS受试者或健康PC中没有发现。此外，两种miRNAs，miR-19 a和19 b，是miR-17的一部分，类似于92簇，被证明下调SOCS-1的表达，SOCS-1是一种在MM中经常沉默的基因，作为IL-6生长信号的抑制剂起着关键作用。我们还鉴定了p300-CBP相关因子，一种参与p53调控的基因，作为miR 106 B（类似于25簇）、miR-181 a和B以及miR-32的真正靶点。使用经miR-19 a和B以及miR-181 a和B拮抗剂处理的人MM细胞系进行的异种移植研究导致裸鼠中肿瘤生长的显著抑制。总之，我们描述了MM miRNA特征，其中包括调节对骨髓瘤发病机制至关重要的蛋白质表达的miRNA。
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 similar to 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 similar to 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 similar to 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 similar to 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.