RSPO2 suppresses colorectal cancer metastasis by counteracting the Wnt5a/Fzd7-driven noncanonical Wnt pathway
RSPO2 suppresses colorectal cancer metastasis by counteracting the Wnt5a/Fzd7-driven noncanonical Wnt pathway
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RSPO2 通过抵消 Wnt5a/Fzd7 驱动的非经典 Wnt 通路来抑制结直肠癌转移
DOI：
10.1016/j.canlet.2017.05.024
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发表时间：
2017-08-28
期刊：
影响因子：
9.7
通讯作者：
Lu, Xincheng
中科院分区：
文献类型：
--
作者：
Dong, Xiaoming;Liao, Wanqin;Lu, Xincheng
r -应答蛋白通过调节Wnt/ β -连环蛋白信号传导，在发育、干细胞存活和致瘤性中发挥关键作用；然而，r -应答蛋白在非典型Wnt信号调节中的作用仍然未知。我们在这里证明了R-spondin 2 （RSPO2）对结直肠癌（CRC）细胞的迁移、侵袭和转移具有抑制作用。在结直肠癌患者中，RSPO2表达降低与肿瘤转移和生存不良相关。RSPO2的转移抑制活性不依赖于Wnt/ β -catenin信号通路，而依赖于fzd7介导的非典型Wnt信号通路。RSPO2和Fzd7的物理相互作用通过znrf3介导的泛素化增加了细胞表面Fzd7的降解，导致下游PKC/ERK信号级联被抑制。在晚期转移癌中，Wnt5a通过阻止Fzd7的降解促进CRC细胞迁移，RSPO2通过阻断Wnt5a与Fzd7受体的结合，拮抗Wnt5a驱动的非规范Wnt信号激活和肿瘤细胞迁移。我们的研究揭示了一种新的RSPO2/Wnt5a竞争的非规范Wnt信号机制，可以调节细胞迁移和侵袭，我们的数据表明，分泌的RSPO2蛋白可以作为Wnt5a/ fzd7驱动的侵袭性结直肠癌肿瘤的潜在治疗方法。(C) 2017 Elsevier B.V.版权所有
R-spondins play critical roles in development, stem cell survival, and tumorigenicity by modulating Wnt/beta-catenin signaling; however, the role of R-spondins in noncanonical Wnt signaling regulation remains largely unknown. We demonstrate here that R-spondin 2 (RSPO2) has an inhibitory effect on colorectal cancer (CRC) cell migration, invasion, and metastasis. Reduced RSPO2 expression was associated with tumor metastasis and poor survival in CRC patients. The metastasis-suppressive activity of RSPO2 was independent of the Wnt/beta-catenin signaling pathway but dependent on the Fzd7-mediated noncanonical Wnt signaling pathway. The physical interaction of RSPO2 and Fzd7 increased the degradation of cell surface Fzd7 via ZNRF3-mediated ubiquitination, which led to the suppression of the downstream PKC/ERK signaling cascade. In late-stage metastatic cancer, Wnt5a promoted CRC cell migration by preventing degradation of Fzd7, and RSPO2 antagonized Wnt5a-driven noncanonical Wnt signaling activation and tumor cell migration by blocking the binding of Wnt5a to the Fzd7 receptor. Our study reveals a novel RSPO2/Wnt5a-competing noncanonical Wnt signaling mechanism that regulates cellular migration and invasion, and our data suggest that secreted RSPO2 protein could serve as a potential therapy for Wnt5a/Fzd7-driven aggressive CRC tumors. (C) 2017 Elsevier B.V. All rights reserved.