EWSR1 overexpression is a pro-oncogenic event in multiple myeloma
EWSR1 overexpression is a pro-oncogenic event in multiple myeloma
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DOI：
10.1007/s12185-020-03027-0
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发表时间：
2020-10-23
影响因子：
2.1
通讯作者：
Kuroda, Junya
中科院分区：
文献类型：
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作者：
Nishiyama, Daichi;Chinen, Yoshiaki;Kuroda, Junya
多发性骨髓瘤(MM)在细胞遗传学、遗传学和分子水平上是异质性的，即使在一个患者的亚克隆之间也是如此，因此，识别分子异常的常见和患者特有的驱动因素是至关重要的。本研究在以往分子水平研究的基础上，对尤文肉瘤断裂区1(EWSR1)基因在MM中的表达模式和功能进行了研究。CD138阳性的骨髓瘤细胞中EWSR1的转录水平在36.4%的未确定意义的单克隆性伽玛病中高于正常浆细胞，在10个人骨髓瘤衍生细胞系(HMCL)中显著高于正常浆细胞。EWSR1基因敲除后，NCI-H929和KMS-12-BM细胞生长受到抑制，细胞凋亡率增加。基因表达谱芯片分析表明，EWSR1基因敲除导致与细胞增殖、细胞运动、细胞代谢和基因表达等过程相关的几个基因的转录调控。特别是，EWSR1基因敲除导致let-7c上调，其已知靶标K-RAS和AKT下调。最后，我们利用社区数据库的分析表明，EWSR1的高表达与MM预后不良和疾病进展呈正相关。这些结果表明，EWSR1的过度表达是一种癌前分子异常，可能参与MM的进展。
Multiple myeloma (MM) is cytogenetically, genetically and molecularly heterogenous even among subclones in one patient, therefore, it is essential to identify both frequent and patient-specific drivers of molecular abnormality. Following previous molecular investigations, we in this study investigated the expression patterns and function of the Ewing sarcoma breakpoint region 1 (EWSR1) gene in MM. The EWSR1 transcriptional level in CD138-positive myeloma cells was higher in 36.4% of monoclonal gammopathy of undetermined significance, in 67.4% of MM patients compared with normal plasma cells, and significantly higher in ten human myeloma-derived cell lines (HMCLs) examined. EWSR1 gene knockdown caused growth inhibition with an increase of apoptotic cells in NCI-H929 and KMS-12-BM cells. Gene expression profiling using microarray analysis suggested EWSR1 gene knockdown caused transcriptional modulation of several genes associated with processes such as cell proliferation, cell motility, cell metabolism, and gene expression. Of particular, EWSR1 gene knockdown caused upregulation of let-7c and downregulation of its known targets K-RAS and AKT. Finally, our analysis using community database suggested that high EWSR1 expression positively associates with poor prognosis and advanced disease stage in MM. These findings suggest that EWSR1 overexpression is a pro-oncogenic molecular abnormality that may participate in MM progression.