RSPO2 suppresses colorectal cancer metastasis by counteracting the Wnt5a/Fzd7-driven noncanonical Wnt pathway.
Cancer Lett
; 402: 153-165, 2017 08 28.
Article
em En
| MEDLINE
| ID: mdl-28600110
ABSTRACT
R-spondins play critical roles in development, stem cell survival, and tumorigenicity by modulating Wnt/ß-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/ß-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.
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1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Colorretais
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Movimento Celular
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Peptídeos e Proteínas de Sinalização Intercelular
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Receptores Frizzled
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Via de Sinalização Wnt
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Proteína Wnt-5a
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Neoplasias Hepáticas
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Neoplasias Pulmonares
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article