Glypican-5 suppresses Epithelial-Mesenchymal Transition of the lung adenocarcinoma by competitively binding to Wnt3a.
Glypican-5 suppresses Epithelial-Mesenchymal Transition of the lung adenocarcinoma by competitively binding to Wnt3a.
复制标题
Glypican-5 通过与 Wnt3a 竞争性结合来抑制肺腺癌的上皮-间质转化。
DOI：
10.18632/oncotarget.12945
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发表时间：
2016-11-29
期刊：
影响因子：
--
通讯作者：
Yin R
中科院分区：
文献类型：
--
作者：
Wang S;Qiu M;Xia W;Xu Y;Mao Q;Wang J;Dong G;Xu L;Yang X;Yin R
GPC5是硫酸乙酰肝素蛋白多糖的一员，是肺腺癌(LAC)中一种新的肿瘤转移抑制因子。然而，GPC5是如何抑制肺癌转移的尚不清楚。在这里，我们发现过表达GPC5在体外诱导了A549细胞显著的上皮-间充质转化(EMT)过程。对RNA测序数据的生物信息学分析表明，GPC5与EMT相关标记物E-钙粘蛋白和Vimentin共表达。过表达β后，WnT/GPC5-连环蛋白信号通路也明显丰富。进一步的体外实验表明，过表达GPC5可以阻断β-连环蛋白从细胞质到细胞核的转位，从而通过与WNT3a的竞争性结合而使WNT/β-连环蛋白信号通路失活。随后的挽救实验表明，当细胞在WNT3a条件培养液中培养时，GPC5诱导的转移表型和EMT过程抑制明显逆转。通过建立严重联合免疫缺陷(SCID)小鼠的转移模型，我们还证明了过表达GPC5抑制LAC迁移，并相应地警告EMT相关标志物，包括上调的E-钙粘素和下调的Vimentin在肺和肝转移中的表达。最后，LAC的临床样本进一步验证了GPC5的表达与E-钙粘蛋白呈正相关，与Twist1和MMP2呈负相关。综上所述，这些数据提示GPC5通过与WNT3a竞争性结合并失活Wnt/β-Catenin信号通路来抑制LAC转移。我们的发现扩大了GPC5在LAC恶性生物学中的作用和分子机制。
We previously demonstrated that Glypican-5 (GPC5), one of the members of heparan sulfate proteoglycan, was a novel tumor metastasis suppressor in lung adenocarcinoma (LAC). However, it remains unclear how GPC5 suppresses lung cancer metastasis. Here, we found over-expression GPC5 induced significant Epithelial-Mesenchymal Transition (EMT) process of A549 cells in vitro. Bioinformatic analysis of RNA sequencing data indicated that GPC5 was co-expressed with EMT related markers, E-cadherin and Vimentin. Wnt/β-catenin signaling pathway was also significantly enriched after overexpressing GPC5. Further in vitro experiments demonstrated that overexpressing GPC5 could block the translocation of β-catenin from cytoplasm to nucleus and therefore inactivate the Wnt/β-catenin signaling pathway by competitively binding to Wnt3a. Subsequent rescue experiments demonstrated that GPC5-induced metastatic phenotype and EMT process suppression were significantly reversed when cells cultured in Wnt3a conditioned media. By establishing the metastatic model in severe combined immune deficiency (SCID) mice, we also demonstrated that overexpressing GPC5 suppressed LAC migration and accordingly alerted EMT related markers, which including up-regulated E-cadherin and down-regulated Vimentin in both lung and liver metastasis. Finally, clinical samples of LAC further validated that GPC5 expression was positively correlated with E-cadherin, and negatively correlated with both Twist1 and MMP2. Taken together, these data suggested that GPC5 is able to suppress the LAC metastasis by competitively binding to Wnt3a and inactivating the Wnt/β-catenin signaling pathway. Our findings expanded the role and the molecular mechanism of GPC5 on malignant bionomics of LAC.