WNT2-Mediated FZD2 Stabilization Regulates Esophageal Cancer Metastasis via STAT3 Signaling
WNT2-Mediated FZD2 Stabilization Regulates Esophageal Cancer Metastasis via STAT3 Signaling
复制标题
WNT2 介导的 FZD2 稳定通过 STAT3 信号调节食管癌转移
DOI：
10.3389/fonc.2020.01168
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发表时间：
2020-07-16
影响因子：
4.7
通讯作者：
Chen, Zhe
中科院分区：
文献类型：
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作者：
Fu, Yufei;Zheng, Qi;Chen, Zhe
食管癌微环境因子WNT2在肿瘤转移中起关键作用。然而，关于WNT2受体及其在ESCC恶性进展中的作用知之甚少。我们进一步研究了WNT2受体之一FZD2在ESCC中的临床意义和潜在的分子机制。通过数据库分析，我们发现临床ESCC标本中FZD2表达与WNT2水平呈正相关。69%（69/100）的ESCC原发病例FZD2表达上调，FZD2表达升高与预后不良显著相关（P < 0.05）。机制上，FZD2通过调控FZD2/STAT3信号通路诱导ESCC细胞迁移和侵袭。体内异种移植实验进一步揭示了FZD2在ESCC中促进转移的作用。此外，我们发现WNT2配体可以通过减弱FZD2泛素化来稳定和磷酸化FZD2受体，从而激活STAT3信号，引发ESCC细胞转移。总的来说，我们的数据揭示了一个新的非规范WNT2/FZD2/STAT3信号轴对ESCC的进展至关重要。针对这一特定信号轴的策略可能用于治疗ESCC患者。
Esophageal cancer micro environment factor WNT2 was critical in cancer metastasis. However, very little is known about WNT2 receptors and their role in the malignant progression of ESCC. The clinical significance and underlying molecular mechanisms of FZD2, one of the receptors of WNT2, was further investigated in ESCC. We found that FZD2 expression was positively correlated with WNT2 levels in clinical ESCC specimens through database analysis. Upregulated FZD2 expression was detected in 69% (69/100) of the primary ESCC cases examined, and increased FZD2 expression was significantly correlated with poor prognosis (P < 0.05). Mechanistically, FZD2 induced the migration and invasion of ESCC cells by regulating the FZD2/STAT3 signaling. In vivo xenograft experiments further revealed the metastasis-promoting role of FZD2 in ESCC. Moreover, we found that the WNT2 ligand could stabilize and phosphorylate the FZD2 receptor by attenuating FZD2 ubiquitination, leading to the activation of STAT3 signaling and the initiation of ESCC cell metastasis. Collectively, our data revealed that a novel non-canonical WNT2/FZD2/STAT3 signaling axis is critical for ESCC progression. Strategies targeting this specific signaling axis might be developed to treat patients with ESCC.