RSPO2-LGR5 signaling has tumour-suppressive activity in colorectal cancer
RSPO2-LGR5 signaling has tumour-suppressive activity in colorectal cancer
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RSPO2-LGR5 信号在结直肠癌中具有肿瘤抑制活性
DOI：
10.1038/ncomms4149
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发表时间：
2014-01-01
影响因子：
16.6
通讯作者：
Lu, Xincheng
中科院分区：
文献类型：
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作者：
Wu, Changjie;Qiu, Sunquan;Lu, Xincheng
R-Spinins是一类分泌的Wnt激动剂家族。家族成员之一的R-响应蛋白2(RSPO2)在胚胎发育、骨形成和肌源性分化中起重要作用；然而，它在人类癌症中的作用尚不清楚。在这里，我们发现由于启动子的超甲基化，RSPO2在人类结直肠癌(CRC)中的表达下调，并且RSPO2的降低与肿瘤的分化、大小和转移有关。RSPO2的过表达抑制了CRC细胞的增殖和致瘤性，而RSPO2的缺失则促进了肿瘤细胞的生长。RSPO2对结直肠癌细胞Wnt/β-catenin信号转导有抑制作用，表现为细胞增殖受抑。在人结肠癌细胞中，RSPO2对Wnt信号的抑制依赖于富含亮氨酸重复序列的G蛋白偶联受体5(LGR5)；RSPO2与LGR5相互作用稳定膜相关锌和环指3(ZNRF3)。我们的数据表明，RSPO2在人类大肠癌中起着肿瘤抑制因子的作用，这些数据揭示了RSPO2诱导的、依赖于LGR5的Wnt信号负反馈环，它对CRC细胞产生净生长抑制效应。
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/beta-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.