Hypoxia-inducible microRNA-210 regulates the DIMT1-IRF4 oncogenic axis in multiple myeloma.
Hypoxia-inducible microRNA-210 regulates the DIMT1-IRF4 oncogenic axis in multiple myeloma.
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DOI：
10.1111/cas.13183
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发表时间：
2017-04
期刊：
影响因子：
5.7
通讯作者：
Tagawa H
中科院分区：
文献类型：
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作者：
Ikeda S;Kitadate A;Abe F;Saitoh H;Michishita Y;Hatano Y;Kawabata Y;Kitabayashi A;Teshima K;Kume M;Takahashi N;Tagawa H
多发性骨髓瘤(MM)的特征是大量恶性浆细胞聚集在骨髓及其微环境中。位于微环境中的低氧生态位导致骨髓瘤细胞变得静止、抗凋亡、糖酵解和未成熟。细胞异质性可能与低氧和常氧条件下不同的基因表达谱有关。在低氧期间，骨髓瘤细胞通过下调干扰素调节因子4(IRF4)获得这些表型，IRF4是骨髓瘤发生过程中必不可少的转录因子。为了确定必要的microRNAs及其在低氧条件下调节的靶点，我们利用低氧暴露的原代MM样本和骨髓瘤细胞系进行了microRNA和cDNA微阵列分析。在低氧条件下，只有miR-210高度上调，并伴随着18S rRNA碱基甲基转移酶DIMT1的直接下调。通过对原始多发性骨髓瘤样本的定量RT-PCR验证了这种反向表达相关性。我们进一步确定DIMT1具有致癌潜力，因为它通过调节IRF4的表达来下调骨髓瘤细胞的致瘤性。值得注意的是，通过分析国家生物技术信息中心数据库中的基因表达综合数据集，我们发现DIMT1的表达随着MM的进展而逐渐增加。总之，通过筛选低氧诱导的microRNA-210靶点，我们确定DIMT1是所有分子亚型MM的新的诊断标记和治疗靶点。
Multiple myeloma (MM) is characterized by the accumulation of a population of malignant plasma cells within the bone marrow and its microenvironment. A hypoxic niche is located within the microenvironment, which causes myeloma cells to become quiescent, anti‐apoptotic, glycolytic, and immature. Cell heterogeneity may be related to distinct gene expression profiles under hypoxic and normoxic conditions. During hypoxia, myeloma cells acquire these phenotypes by downregulating interferon regulatory factor 4 (IRF4), an essential transcription factor in myeloma oncogenesis. To identify essential microRNAs and their targets regulated under hypoxic conditions, we undertook microRNA and cDNA microarray analyses using hypoxia‐exposed primary MM samples and myeloma cell lines. Under hypoxia, only miR‐210 was highly upregulated and was accompanied by direct downregulation of an 18S rRNA base methyltransferase, DIMT1. This inverse expression correlation was validated by quantitative RT‐PCR for primary MM samples. We further determined that DIMT1 has an oncogenic potential as its knockdown reduced tumorigenicity of myeloma cells through regulation of IRF4 expression. Notably, by analyzing gene expression omnibus datasets in the National Center for Biotechnology Information database, we found that DIMT1 expression increased gradually with MM progression. In summary, by screening for targets of hypoxia‐inducible microRNA‐210, we identified DIMT1 as a novel diagnostic marker and therapeutic target for all molecular subtypes of MM.