WNT5A: a motility-promoting factor in Hodgkin lymphoma
WNT5A: a motility-promoting factor in Hodgkin lymphoma
复制标题
DOI：
10.1038/onc.2016.183
复制
发表时间：
2017-01-05
期刊：
影响因子：
8
通讯作者：
Kube, D.
中科院分区：
文献类型：
--
作者：
Linke, F.;Zaunig, S.;Kube, D.
经典霍奇金淋巴瘤（cHL）具有典型的临床表现，其播散累及功能性邻近淋巴结。参与淋巴瘤细胞扩散的因素尚不清楚。本研究表明，与非霍奇金淋巴瘤细胞系相比，cHL细胞系的迁移率更高。豪猪抑制剂WNT -059/IWP-2抑制WNT分泌，表明cHL细胞的迁移、侵袭和粘附依赖于自分泌的WNT信号，但不影响细胞增殖。重组WNT5A或过表达WNT5A可刺激cHL细胞迁移，而WNT10A、WNT1OB和WNT16均无此作用。延时研究揭示了一种由WNT5A调节的变形虫型细胞迁移。使用豪猪抑制剂或WNT5A拮抗剂，观察到cHL细胞的迁移距离和速度降低，以及运动模式改变。frzzled5和Dishevelled3的敲低破坏了wnt5a介导的RHOA激活和细胞迁移。过表达DVL3-K435M或Y-27632/H1152P抑制ROCK （rho相关蛋白激酶）会破坏cHL细胞的迁移。除了这些体外研究WNT5A作用的机制外，全球基因表达数据显示，与正常b细胞亚群和其他淋巴瘤相比，原代HL细胞中的WNT5A表达增加。此外，在鸡绒毛膜尿囊膜实验中，豪猪蛋白和WNT5A在cHL细胞中的活性都对淋巴瘤的发生有影响。WNT -059抑制WNT分泌后，这些淋巴瘤的大出血明显减少。因此，我们提出了一个模型，其中WNT信号在调节肿瘤促进过程中发挥重要作用。
Classical Hodgkin lymphoma (cHL) has a typical clinical manifestation, with dissemination involving functionally neighboring lymph nodes. The factors involved in the spread of lymphoma cells are poorly understood. Here we show that cHL cell lines migrate with higher rates compared with non -Hodgkin lymphoma cell lines. cHL cell migration, invasion and adhesion depend on autocrine WNT signaling as revealed by the inhibition of WNT secretion with the porcupine inhibitors Wnt-059/IWP-2, but did not affect cell proliferation. While application of recombinant WNT5A or WNT5A overexpression stimulates cHL cell migration, neither WNT10A, WNT1OB nor WNT16 did so. Time-lapse studies revealed an amoeboid type of cell migration modulated by WNT5A. Reduced migration distances and velocity of cHL cells, as well as altered movement patterns, were observed using porcupine inhibitor or WNT5A antagonist. Knockdown of Frizzled5 and Dishevelled3 disrupted the WNT5A-mediated RHOA activation and cell migration. Overexpression of DVL3-K435M or inhibition of ROCK (Rho-associated protein kinase) by Y-27632/H1152P disrupted cHL cell migration. In addition to these mechanistic insights into the role of WNT5A in vitro, global gene expression data revealed an increased WNT5A expression in primary HL cells in comparison with normal B-cell subsets and other lymphomas. Furthermore, the activity of both porcupine and WNT5A in cHL cells had an impact on lymphoma development in the chick chorionallantoic membrane assay. Massive bleeding of these lymphomas was significantly reduced after inhibition of WNT secretion by Wnt-059. Therefore, a model is proposed where WNT signaling has an important role in regulating tumor-promoting processes.