Abstract
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.
Keywords:
Colorectal cancer; Fzd7; Metastasis; RSPO2; Wnt5a.
Copyright © 2017 Elsevier B.V. All rights reserved.
MeSH terms
-
Adenovirus E1A Proteins / genetics
-
Adenovirus E1A Proteins / metabolism
-
Animals
-
Binding, Competitive
-
Cell Line, Tumor
-
Cell Movement*
-
Colorectal Neoplasms / genetics
-
Colorectal Neoplasms / metabolism*
-
Colorectal Neoplasms / pathology
-
Extracellular Signal-Regulated MAP Kinases / metabolism
-
Frizzled Receptors / genetics
-
Frizzled Receptors / metabolism*
-
Humans
-
Hyaluronan Receptors / genetics
-
Hyaluronan Receptors / metabolism
-
Intercellular Signaling Peptides and Proteins / genetics
-
Intercellular Signaling Peptides and Proteins / metabolism*
-
Liver Neoplasms / genetics
-
Liver Neoplasms / metabolism*
-
Liver Neoplasms / secondary
-
Lung Neoplasms / genetics
-
Lung Neoplasms / metabolism*
-
Lung Neoplasms / secondary
-
Male
-
Matrix Metalloproteinase 7 / genetics
-
Matrix Metalloproteinase 7 / metabolism
-
Mice, Nude
-
Neoplasm Invasiveness
-
Protein Binding
-
Protein Kinase C / metabolism
-
Protein Stability
-
Proteolysis
-
Proto-Oncogene Proteins / genetics
-
Proto-Oncogene Proteins / metabolism
-
Proto-Oncogene Proteins c-ets
-
RNA Interference
-
Time Factors
-
Transfection
-
Ubiquitin-Protein Ligases / genetics
-
Ubiquitin-Protein Ligases / metabolism
-
Ubiquitination
-
Wnt Signaling Pathway*
-
Wnt-5a Protein / metabolism*
Substances
-
Adenovirus E1A Proteins
-
CD44 protein, human
-
ETV4 protein, human
-
FZD7 protein, human
-
Frizzled Receptors
-
Hyaluronan Receptors
-
Intercellular Signaling Peptides and Proteins
-
Proto-Oncogene Proteins
-
Proto-Oncogene Proteins c-ets
-
Rspo2 protein, human
-
WNT5A protein, human
-
Wnt-5a Protein
-
Ubiquitin-Protein Ligases
-
ZNRF3 protein, human
-
Protein Kinase C
-
Extracellular Signal-Regulated MAP Kinases
-
MMP7 protein, human
-
Matrix Metalloproteinase 7