RSPO2-LGR5 signaling has tumour-suppressive activity in colorectal cancer.
R-spondins are a family of secreted Wnt agonists. One of the family members, R-spondin 2 (RSPO2), has an important role in embryonic development, bone formation and myogenic differentiation; however, its role in human cancers remains largely unknown. Here we show that RSPO2 expression is downregulated in human colorectal cancers (CRCs) due to promoter hypermethylation, and that the RSPO2 reduction correlates with tumour differentiation, size and metastasis. Overexpression of RSPO2 suppresses CRC cell proliferation and tumorigenicity, whereas the depletion of RSPO2 enhances tumour cell growth. RSPO2 has an inhibitory effect on Wnt/β-catenin signaling in the CRC cells that show suppressed cell proliferation. In human CRC cells, the RSPO2-induced inhibition of Wnt signaling depends on leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5); RSPO2 interacts with LGR5 to stabilize the membrane-associated zinc and ring finger 3 (ZNRF3). Our data suggest that RSPO2 functions as a tumour suppressor in human CRCs, and these data reveal a RSPO2-induced, LGR5-dependent Wnt signaling-negative feedback loop that exerts a net growth-suppressive effect on CRC cells.
1] Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325000, China [2].
Changjie
C
Wu
1] Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325000, China [2].
Sunquan
S
Qiu
1] Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325000, China [2].
Liting
L
Lu
Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325000, China.
Jiawei
J
Zou
The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
Wen-feng
WF
Li
The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
Ouchen
O
Wang
Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325000, China.
Haina
H
Zhao
Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325000, China.
Hongxiao
H
Wang
Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325000, China.
Jiajia
J
Tang
Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325000, China.
Lin
L
Chen
Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325000, China.
Tao
T
Xu
1] Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325000, China [2] Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China.
Zhongsheng
Z
Sun
Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325000, China.
Wanqin
W
Liao
Departments of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Guangbin
G
Luo
Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325000, China.
Xincheng
X
Lu
D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction; D000098907:R-Spondins
D036341:Intercellular Signaling Peptides and Proteins; D043562:Receptors, G-Protein-Coupled; C116884:LGR5 protein, human; C557408:Rspo2 protein, human; D000098907:R-Spondins