RSPO2–LGR5 signaling has tumour-suppressive activity in colorectal cancer

Changjie Wu, Sunquan Qiu, Liting Lu, Jiawei Zou, Wen-feng Li, Ouchen Wang, Haina Zhao, Hongxiao Wang, Jiajia Tang, Lin Chen, Tao Xu, Zhongsheng Sun, Wanqin Liao, Guangbin Luo and Xincheng Lu ()
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Changjie Wu: Institute of Genomic Medicine, Wenzhou Medical University
Sunquan Qiu: Institute of Genomic Medicine, Wenzhou Medical University
Liting Lu: Institute of Genomic Medicine, Wenzhou Medical University
Jiawei Zou: Institute of Genomic Medicine, Wenzhou Medical University
Wen-feng Li: The First Affiliated Hospital of Wenzhou Medical University
Ouchen Wang: The First Affiliated Hospital of Wenzhou Medical University
Haina Zhao: Institute of Genomic Medicine, Wenzhou Medical University
Hongxiao Wang: Institute of Genomic Medicine, Wenzhou Medical University
Jiajia Tang: Institute of Genomic Medicine, Wenzhou Medical University
Lin Chen: Institute of Genomic Medicine, Wenzhou Medical University
Tao Xu: Institute of Genomic Medicine, Wenzhou Medical University
Zhongsheng Sun: Institute of Genomic Medicine, Wenzhou Medical University
Wanqin Liao: Institute of Genomic Medicine, Wenzhou Medical University
Guangbin Luo: Case Western Reserve University
Xincheng Lu: Institute of Genomic Medicine, Wenzhou Medical University

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: Abstract 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.

Date: 2014
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DOI: 10.1038/ncomms4149

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