WNT7a induces E-cadherin in lung cancer cells
WNT7a induces E-cadherin in lung cancer cells
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DOI：
10.1073/pnas.1734137100
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发表时间：
2003-09-02
影响因子：
11.1
通讯作者：
Drabkin, HA
中科院分区：
文献类型：
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作者：
Ohira, T;Gemmill, RM;Drabkin, HA
癌症中的E-钙粘蛋白丢失与去分化、侵袭和转移相关。果蝇DE-钙粘蛋白受Wnt/β-连环蛋白信号转导的调节，尽管这在哺乳动物细胞中尚未得到证实。我们以前报道过3 p25编码的WNT 7a在肺癌中的表达经常下调，而E-cadherin或β-catenin的缺失是预后不良的特征。在这里，我们表明，WNT 7a既激活E-cadherin表达通过β-连环蛋白特异性机制在肺癌细胞中，并参与了一个积极的反馈回路。Li+是一种GSK 3 β抑制剂，以非肌醇依赖的方式诱导E-钙粘蛋白。类似地，暴露于mWNT 7a特异性诱导游离β-连环蛋白和E-钙粘蛋白。在已知的E-cadherin的转录抑制因子中，ZEB 1与肺癌细胞系中E-cadherin的丢失唯一相关，并且其通过RNA干扰的抑制导致E-cadherin的诱导。E-钙粘蛋白和WNT 7a损失的药理学逆转通过Li+、组蛋白脱乙酰酶抑制剂或在某些情况下仅通过组合抑制剂实现。我们的研究结果提供了支持，即通过WNT/β-连环蛋白信号传导诱导E-钙粘蛋白是在肺癌细胞中起作用的进化上保守的途径，并且WNT 7a表达的丧失可能通过其对E-钙粘蛋白的影响在肺癌的发展或进展中是重要的。
E-cadherin loss in cancer is associated with de-differentiation, invasion, and metastasis. Drosophila DE-cadherin is regulated by Wnt/beta-catenin signaling, although this has not been demonstrated in mammalian cells. We previously reported that expression of WNT7a, encoded on 3p25, was frequently down-regulated in lung cancer, and that loss of E-cadherin or beta-catenin was a poor prognostic feature. Here we show that WNT7a both activates E-cadherin expression via a beta-catenin specific mechanism in lung cancer cells and is involved in a positive feedback loop. Li+, a GSK3beta inhibitor, led to E-cadherin induction in an inositol-independent manner. Similarly, exposure to mWNT7a specifically induced free beta-catenin and E-cadherin. Among known transcriptional suppressors of E-cadherin, ZEB1 was uniquely correlated with E-cadherin loss in lung cancer cell lines, and its inhibition by RNA interference resulted in E-cadherin induction. Pharmacologic reversal of E-cadherin and WNT7a losses was achieved with Li+, histone deacetylase inhibition, or in some cases only with combined inhibitors. Our findings provide support that E-cadherin induction by WNT/beta-catenin signaling is an evolutionarily conserved pathway operative in lung cancer cells, and that loss of WNT7a expression may be important in lung cancer development or progression by its effects on E-cadherin.