Inhibition of CCN6 (Wnt-1-induced signaling protein 3) down-regulates E-cadherin in the breast epithelium through induction of snail and ZEB1
Inhibition of CCN6 (Wnt-1-induced signaling protein 3) down-regulates E-cadherin in the breast epithelium through induction of snail and ZEB1
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DOI：
10.2353/ajpath.2008.070899
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发表时间：
2008-04-01
影响因子：
6
通讯作者：
Kleer, Celina G.
中科院分区：
文献类型：
--
作者：
Huang, Wei;Zhang, Yanhong;Kleer, Celina G.
富含半胱氨酸的蛋白CCN6[或WNT-1诱导的信号蛋白3(WISP3)]在侵袭性炎症性乳腺癌中发挥肿瘤抑制作用。CCN6的缺失与分化较差的表型和侵袭性增加有关。在这里，我们发现CCN6的表达减少发生在60%的浸润性乳腺癌中，并且与腋窝淋巴结转移有关。此外，浸润性癌组织中CCN6的低表达与E-钙粘附素的表达降低有关。在体外，在两个良性的人乳腺上皮细胞系(HME和MCF10A)中，CCN6的RNA干扰敲除降低了E-cadherin蛋白和mRNA的表达，并降低了E-cadherin启动子的活性；这种减少依赖于完整的E-box元件。染色质免疫沉淀分析显示，CCN6基因敲除HME细胞后，E-钙粘蛋白转录抑制基因Snail和ZEB1上调，并增强了它们与E-钙粘蛋白启动子的结合和募集。小干扰RNA介导的ZEB1或Snail基因敲除可阻断CCN6抑制引起的E-钙粘蛋白表达下调。这些数据首次表明，在相当数量的浸润性乳腺癌中，CCN6的表达减少或丢失，并且CCN6调节E-钙粘素的转录抑制物。综上所述，我们的结果导致了一个新的假设，即Snail和ZEB1位于CCN6的下游，在CCN6介导的乳腺癌E-钙粘素调控中发挥关键作用。
The cysteine-rich protein CCN6 [or Wnt-1-induced signaling protein 3 (WISP3)] exerts tumor-suppressive effects in aggressive inflammatory breast cancer. Loss of CCN6 is associated with poorly differentiated phenotypes and increased invasion. Here, we show that reduction of CCN6 expression occurs in 60% of invasive breast carcinomas and is associated with axillary lymph node metastases. Furthermore, low CCN6 expression in invasive carcinoma tissue samples correlates with reduced expression of E-cadherin. In vitro, RNA interference knockdown of CCN6 in two benign human mammary epithelial cell lines (HME and MCF10A) decreased expression of E-cadherin protein and mRNA and reduced activity of the E-cadherin promoter; this reduction was dependent on intact E-box elements. CCN6 knockdown in HME cells resulted in up-regulation of the E-cadherin transcriptional repressors Snail and ZEB1 and enhanced their recruitment and binding to the E-cadherin promoter as analyzed by chromatin immunoprecipitation assays. Small interfering RNA-mediated knockdown of ZEB1 or Snail blocked the down-regulation of E-cadherin caused by CCN6 inhibition. These data show, for the first time, that CCN6 expression is reduced or lost in a substantial number of invasive breast carcinomas and that CCN6 modulates transcriptional repressors of E-cadherin. Together, our results lead to a new hypothesis that Snail and ZEB1 are downstream of CCN6 and play a critical role in CCN6-mediated regulation of E-cadherin in breast cancer.