文章：

小GTP酶RhoU位于JAK/STAT信号通路的下游，并介导多发性骨髓瘤中的细胞迁移

The small GTPase RhoU lays downstream of JAK/STAT signaling and mediates cell migration in multiple myeloma

原文发布日期：2018-02-13

DOI: 10.1038/s41408-018-0053-z

类型: Article

开放获取: 是

英文摘要：

Multiple myeloma is a post-germinal center B-cell neoplasm, characterized by the proliferation of malignant bone marrow plasma cells, whose survival and proliferation is sustained by growth factors and cytokines present in the bone marrow microenvironment. Among them, IL-6 triggers the signal downstream of its receptor, leading to the activation of the JAK/STAT pathway. The atypical GTPase RhoU lays downstream of STAT3 transcription factor and could be responsible for mediating its effects on cytoskeleton dynamics. Here we demonstrate that RHOU is heterogeneously expressed in primary multiple myeloma cells and significantly modulated with disease progression. At the mRNA level, RHOU expression in myeloma patients correlated with the expression of STAT3 and its targets MIR21 and SOCS3. Also, IL-6 stimulation of human myeloma cell lines up-regulated RHOU through STAT3 activation. On the other hand, RhoU silencing led to a decrease in cell migration with the accumulation of actin stress fibers, together with a decrease in cyclin D2 expression and in cell cycle progression. Furthermore, we found that even though lenalidomide positively regulated RhoU expression leading to higher cell migration rates, it actually led to cell cycle arrest probably through a p21 dependent mechanism. Lenalidomide treatment in combination with RhoU silencing determined a loss of cytoskeletal organization inhibiting cell migration, and a further increase in the percentage of cells in a resting phase. These results unravel a role for RhoU not only in regulating the migratory features of malignant plasma cells, but also in controlling cell cycle progression.

摘要翻译： 

多发性骨髓瘤是一种生发中心后B细胞肿瘤，其特征是恶性骨髓浆细胞的增殖，这些细胞的存活和增殖依赖于骨髓微环境中存在的生长因子和细胞因子。其中，IL-6触发其受体下游信号，导致JAK/STAT通路激活。非典型GTP酶RhoU位于STAT3转录因子下游，可能介导其对细胞骨架动力学的影响。本研究证明RHOU在原代多发性骨髓瘤细胞中异质性表达，并随疾病进展显著调节。在mRNA水平上，骨髓瘤患者RHOU表达与STAT3及其靶标MIR21、SOCS3表达相关。IL-6刺激人骨髓瘤细胞系通过STAT3激活上调了RHOU。另一方面，RhoU沉默导致细胞迁移减少并伴随应激纤维积聚，同时细胞周期蛋白D2表达下降及细胞周期进程受阻。此外，我们发现尽管来那度胺正向调控RhoU表达导致细胞迁移率升高，但通过p21依赖性机制实际引发了细胞周期阻滞。来那度胺联合RhoU沉默处理导致细胞骨架结构紊乱从而抑制细胞迁移，并进一步增加静止期细胞比例。这些结果揭示了RhoU不仅调控恶性浆细胞的迁移特性，还参与细胞周期进程的调控。

原文链接：

The small GTPase RhoU lays downstream of JAK/STAT signaling and mediates cell migration in multiple myeloma