Dong Xiaoming, Liao Wanqin, Zhang Li, Tu Xi, Hu Jin, Chen Tianke, Dai Xiaowei, Xiong Yan, Liang Weicheng, Ding Chaodong, Liu Rui, Dai Juji, Wang Ouchen, Lu Liting, Lu Xincheng
School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325000, China.
Department of Clinical Laboratory, Taizhou Hospital of Zhejiang Province, Zhejiang, 317000, China.
Cancer Lett. 2017 Aug 28;402:153-165. doi: 10.1016/j.canlet.2017.05.024. Epub 2017 Jun 6.
R-spondins play critical roles in development, stem cell survival, and tumorigenicity by modulating Wnt/β-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/β-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.
R-spondins通过调节Wnt/β-连环蛋白信号通路在发育、干细胞存活和肿瘤发生中发挥关键作用；然而，R-spondins在非经典Wnt信号通路调节中的作用仍 largely未知。我们在此证明，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。RSPO2表达降低与CRC患者的肿瘤转移和不良生存相关。RSPO2的转移抑制活性独立于Wnt/β-连环蛋白信号通路，但依赖于Fzd7介导的非经典Wnt信号通路。RSPO2与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，从而导致下游PKC/ERK信号级联的抑制。在晚期转移性癌症中，Wnt5a通过阻止Fzd7的降解促进CRC细胞迁移，而RSPO2通过阻断Wnt5a与Fzd7受体的结合拮抗Wnt5a驱动的非经典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竞争性非经典Wnt信号机制，该机制调节细胞迁移和侵袭，我们的数据表明分泌的RSPO2蛋白可作为Wnt5a/Fzd7驱动的侵袭性CRC肿瘤的潜在治疗方法。
