Abstract Multiple myeloma (MM) is a serious health issue in hematological malignancies. Long non-coding RNA taurine-upregulated gene 1 (TUG1) has been reported to be highly expressed in the plasma of MM patients. However, the functions of TUG1 in MM tumorigenesis along with related molecular basis are still undefined. In this study, increased TUG1 and decreased microRNA-34a-5p (miR-34a-5p) levels in MM tissues and cells were measured by the real-time quantitative polymerase reaction assay. The expression of relative proteins was determined by the Western blot assay. TUG1 knockdown suppressed cell viability, induced cell cycle arrest and cell apoptosis in MM cells, as shown by Cell Counting Kit-8 and flow cytometry assays. Bioinformatics analysis, luciferase reporter assay, and RNA pull-down assay indicated that miR-34a-5p was a target of TUG1 and directly bound to notch receptor 1 (NOTCH1), and TUG1 regulated the NOTCH1 expression by targeting miR-34a-5p. The functions of miR-34a-5p were abrogated by TUG1 upregulation. Moreover, TUG1 loss impeded MM xenograft tumor growth in vivo by upregulating miR-34a-5p and downregulating NOTCH1. Furthermore, TUG1 depletion inhibited the expression of Hes-1, Survivin, and Bcl-2 protein in MM cells and xenograft tumors. TUG1 knockdown inhibited MM tumorigenesis by regulating the miR-34a-5p/NOTCH1 signaling pathway in vitro and in vivo, deepening our understanding of the TUG1 function in MM.

中文翻译：

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长非编码RNA TUG1敲低通过调节microRNA-34a-5p/NOTCH1信号通路阻碍多发性骨髓瘤的肿瘤发生


摘要 多发性骨髓瘤（MM）是血液系统恶性肿瘤中的一个严重的健康问题。据报道，长链非编码 RNA 牛磺酸上调基因 1 (TUG1) 在 MM 患者血浆中高表达。然而，TUG1 在 MM 肿瘤发生中的功能以及相关的分子基础仍不清楚。在本研究中，通过实时定量聚合酶反应测定测量了 MM 组织和细胞中 TUG1 的增加和 microRNA-34a-5p (miR-34a-5p) 水平的降低。通过Western blot测定相关蛋白的表达。 Cell Counting Kit-8 和流式细胞术检测显示，TUG1 敲低可抑制 MM 细胞的细胞活力，诱导细胞周期停滞和细胞凋亡。生物信息学分析、荧光素酶报告基因分析和RNA Pull-down分析表明，miR-34a-5p是TUG1的靶点，并直接与Notch受体1（NOTCH1）结合，并且TUG1通过靶向miR-34a-5p来调节NOTCH1的表达。 TUG1 上调消除了 miR-34a-5p 的功能。此外，TUG1 缺失通过上调 miR-34a-5p 和下调 NOTCH1 阻碍体内 MM 异种移植肿瘤的生长。此外，TUG1 缺失抑制了 MM 细胞和异种移植肿瘤中 Hes-1、Survivin 和 Bcl-2 蛋白的表达。 TUG1 敲低通过在体外和体内调节 miR-34a-5p/NOTCH1 信号通路抑制 MM 肿瘤发生，加深了我们对 TUG1 在 MM 中功能的理解。