Wnt5a induces and maintains prostate cancer cells dormancy in bone
Wnt5a induces and maintains prostate cancer cells dormancy in bone
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Wnt5a 诱导并维持前列腺癌细胞在骨中的休眠
DOI：
10.1084/jem.20180661
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发表时间：
2019-02-01
影响因子：
15.3
通讯作者：
Song, Libing
中科院分区：
文献类型：
--
作者：
Ren, Dong;Dai, Yuhu;Song, Libing
在相当一部分前列腺癌（PCa）患者中，骨转移在数年甚至数十年的潜伏期后出现。已经提出典型的Wnt/β-连环蛋白信号传导与癌细胞的休眠有关。然而，这些肿瘤细胞如何在来自骨微环境的Wnt/β-连环蛋白信号传导的控制下保持休眠和复发仍然未知。在这里，我们报告说，Wnt 5a从成骨细胞龛诱导休眠PCa细胞在体外和体内通过诱导Siah E3泛素蛋白连接酶2（SIAH 2）的表达，抑制Wnt/β-连环蛋白信号在可逆的方式。此外，Wnt 5a诱导的PCa细胞休眠的这种作用依赖于受体酪氨酸激酶样孤儿受体2（ROR 2），并且在PCa患者中观察到ROR 2表达与无骨转移生存率呈负相关。因此，这些结果表明Wnt 5a/ROR 2/SIAH 2信号传导轴在诱导和维持骨中PCa细胞休眠中起关键作用，表明Wnt 5a通过诱导骨中PCa细胞休眠的潜在治疗用途。
In a substantial fraction of prostate cancer (PCa) patients, bone metastasis appears after years or even decades of latency. Canonical Wnt/beta-catenin signaling has been proposed to be implicated in dormancy of cancer cells. However, how these tumor cells are kept dormant and recur under control of Wnt/beta-catenin signaling derived from bone microenvironment remains unknown. Here, we report that Wnt5a from osteoblastic niche induces dormancy of PCa cells in a reversible manner in vitro and in vivo via inducing Siah E3 Ubiquitin Protein Ligase 2 (SIAH2) expression, which represses Wnt/beta-catenin signaling. Furthermore, this effect of Wnt5a-induced dormancy of PCa cells depends on receptor tyrosine kinase-like orphan receptor 2 (ROR2), and a negative correlation of ROR2 expression with bone metastasis-free survival is observed in PCa patients. Therefore, these results demonstrate that Wnt5a/ROR2/SIAH2 signaling axis plays a crucial role in inducing and maintaining PCa cells dormancy in bone, suggesting a potential therapeutic utility of Wnt5a via inducing dormancy of PCa cells in bone.