Journal
CANCER LETTERS
Volume 402, Issue -, Pages 153-165Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2017.05.024
Keywords
RSPO2; Colorectal cancer; Metastasis; Fzd7; Wnt5a
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Funding
- National Natural Science Foundation of China [81572826, 81372490, 81472556, 81501978]
- Zhejiang Provincial Natural Science Foundation [LZ14H160003]
- Zhejiang Provincial Program for the Cultivation of High-Level Innovative Health Talents
- Zhejiang Public Welfare Technologies Research [2014C33257]
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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.
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