Bortezomib-inducible long non-coding RNA myocardial infarction associated transcript is an oncogene in multiple myeloma that suppresses miR-29b
Bortezomib-inducible long non-coding RNA myocardial infarction associated transcript is an oncogene in multiple myeloma that suppresses miR-29b
复制标题
硼替佐米诱导的长非编码RNA心肌梗死相关转录本是多发性骨髓瘤中抑制miR-29b的癌基因
DOI：
10.1038/s41419-019-1551-z
复制
发表时间：
2019-04-09
影响因子：
9
通讯作者：
Luo, Yanwei
中科院分区：
文献类型：
--
作者：
Fu, Yunfeng;Liu, Xiao;Luo, Yanwei
由于使用蛋白酶体抑制剂如硼替佐米（BTZ），多发性骨髓瘤（MM）患者的临床结局在过去十年中使总生存期几乎翻了一番。然而，一些MM患者对BTZ产生原发性耐药，而另一些患者在治疗后产生耐药。在这项研究中，我们研究了BTZ耐药和MM患者长链非编码RNA（lncRNA）功能障碍之间的关系。从MM患者和健康供体中收集骨髓样本进行lncRNA微阵列和生存分析。为了研究MM中lncRNA介导的BTZ耐药的功能和潜在机制，我们对携带肿瘤异种移植物的裸鼠和临床样本进行了CCK-8测定、流式细胞术分析、双荧光素酶报告基因测定和RNA下拉测定。与健康对照组相比，MM患者中差异表达的lncRNA心肌梗死相关转录物（MIAT）高度表达，并预测不良生存结局。此外，与新诊断的MM患者相比，MIAT表达在BTZ耐药的MM患者中显著增加，并被鉴定为BTZ诱导的lncRNA。具体而言，BTZ通过增加stat 1磷酸化上调MIAT表达。沉默MIAT抑制MM细胞生长，并通过负调节miR-29 b使MM细胞对BTZ敏感。我们的数据证明了MIAT作为MM患者克服BTZ耐药的工具的实用性。
Clinical outcomes of patients with multiple myeloma (MM) have almost doubled the overall survival over the last decade owing to the use of proteasome inhibitor such as bortezomib (BTZ). However, some patients with MM develop primary resistance to BTZ, whereas others develop resistance after treatment. In this study, we investigated relationships between BTZ resistance and dysfunction of long non-coding RNAs (lncRNAs) in patients with MM. Bone marrow samples were collected from patients with MM and healthy donors for lncRNA microarray and survival analyses. To investigate functions and underlying mechanisms of lncRNA-mediated BTZ resistance in MM, we performed CCK-8 assays, flow cytometry analyses, dual luciferase report gene assays, and RNA pulldown assays with samples from nude mice carrying tumor xenografts and in clinical samples. Differentially expressed lncRNA myocardial infarction associated transcripts (MIAT) were highly expressed in patients with MM compared with healthy controls, and were predictive of poor survival outcomes. Moreover, MIAT expression was significantly increased in BTZ-resistant patients with MM compared with newly diagnosed patients with MM, and was identified as a BTZ-inducible lncRNA. Specifically, BTZ upregulated MIAT expression through increased stat1 phosphorylation. Silencing of MIAT inhibited MM cell growth and sensitized MM cells to BTZ by negatively regulating miR-29b. Our data demonstrated the utility of MIAT as a tool for overcoming BTZ resistance in patients with MM.