R-spondin 2-LGR4 system regulates growth, migration and invasion, epithelial-mesenchymal transition and stem-like properties of tongue squamous cell carcinoma via Wnt/beta-catenin signaling
R-spondin 2-LGR4 system regulates growth, migration and invasion, epithelial-mesenchymal transition and stem-like properties of tongue squamous cell carcinoma via Wnt/beta-catenin signaling
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R-spondin 2-LGR4系统通过Wnt/β-catenin信号调节舌鳞状细胞癌的生长、迁移和侵袭、上皮间质转化和干细胞样特性
DOI：
10.1016/j.ebiom.2019.03.076
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发表时间：
2019
期刊：
影响因子：
11.1
通讯作者：
Cheng Bin
中科院分区：
文献类型：
--
作者：
Zhang Liping;Song Yan;Ling Zihang;Li Yuanyuan;Ren Xianyue;Yang Jing;Wang Zhi;Xia Juan;Zhang Weizhen;Cheng Bin
背景R-spondins（Rspo）和富含亮氨酸重复序列的G蛋白偶联受体（LGR）通过激活Wnt信号通路在发育、干细胞存活和致瘤性中发挥重要作用。R-spondins-LGR信号传导是否影响鳞状细胞癌（SCC）的进展仍不清楚。本研究旨在探讨R-spodin 2/LGR 4在舌鳞癌（tongue SCC，TSCC）中的作用。通过药理学和遗传学方法改变Rspo 2或LGR 4的水平，并评估对TSCC进展的影响。其水平与舌鳞癌的淋巴结转移、临床分期及生存率密切相关。外源性Rspo 2或Rspo 2过表达促进了体内外SCC的生长、迁移和侵袭、上皮-间质转化（EMT）和干细胞样特性。Rspo 2的沉默消除了这些表型。在TSCC中，Rspo 2功能性上调LGR 4。在TSCC细胞系中，Rspo 2过表达增加，而Rspo 2沉默降低LGR 4的表达，导致随后的LRP 6磷酸化和β-catenin的核转位。结论：β-catenin的核转位与β-catenin下游转录因子TCF-1及其靶基因CD 44、CyclinD 1和c-Myc的表达改变有关，Rspo 2-LGR 4系统通过Wnt/β-catenin信号通路调控TSCC的生长、迁移和侵袭、EMT和干细胞样特性。
BackgroundR-spondins (Rspo) and leucine-rich repeat-containing G-protein-coupled receptors (LGR) play important roles in development, stem cells survival, and tumorigenicity by activating Wnt signaling pathway. Whether R-spondins-LGR signaling affects the progression of squamous cell carcinoma (SCC) remain unknown. This study aims to uncover the role of R-spodin2/LGR4 in tongue SCC (TSCC).MethodsThe expression of Rspo2 in TSCC specimens and its correlation with TSCC clinical outcome were evaluated. Levels of Rspo2 or LGR4 were altered by pharmacological and genetic approaches, and the effects on TSCC progression were assessed.FindingsAberrantly high levels of Rspo2 were detected in TSCC specimens. Its levels were closely related with lymph node metastasis, clinical stage and survival rate in patients with tongue SCC. Exogenous Rspo2 or overexpression of Rspo2 promoted growth, migration and invasion, epithelial-mesenchymal transition (EMT) and stem-like properties in SCC both in vivo and in vitro. Silence of Rspo2 abolished these phenotypes. LGR4 was functionally upregulated by Rspo2 in TSCC. Overexpression of Rspo2 increased, whereas Rspo2 silencing decreased the expression of LGR4, leading to subsequent phosphorylation of LRP6 and nuclear translocation of β-catenin in TSCC cell lines. This nuclear translocation of β-catenin was associated with a significant alteration in TCF-1, a downstream nuclear transcription factor of β-catenin, as well as its target genes: CD44, CyclinD1 and c-Myc.InterpretationRspo2-LGR4 system regulates growth, migration and invasion, EMT and stem-like properties of TSCC via Wnt/β-catenin signaling pathway.