A self-enforcing CD44s/ZEB1 feedback loop maintains EMT and stemness properties in cancer cells
A self-enforcing CD44s/ZEB1 feedback loop maintains EMT and stemness properties in cancer cells
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DOI：
10.1002/ijc.29642
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发表时间：
2015-12-01
影响因子：
6.4
通讯作者：
Stemmler, Marc P.
中科院分区：
文献类型：
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作者：
Preca, Bogdan-Tiberius;Bajdak, Karolina;Stemmler, Marc P.
癌的侵袭和转移通常是通过诱导异常的上皮-间充质转化(EMT)来激活的。这主要是由转录因子ZEB1驱动的，促进肿瘤启动能力与假定的干细胞标记CD44表达增加相关。然而，ZEB1、CD44与肿瘤发生之间的直接联系仍是个谜。值得注意的是，EMT诱导的ESRP1抑制控制着CD44的选择性剪接，导致表达从变异的CD44v转变为标准的CD44s亚型。我们分析了CD44和ZEB1是否相互调控，表明在乳腺癌和胰腺癌中，ZEB1通过抑制ESRP1来控制CD44S的剪接。有趣的是，CD44s本身激活了ZEB1的表达，导致了ZEB1和CD44s的自我维持表达。这种新的CD44S-ZEB1调控环的激活对肿瘤细胞具有功能影响，表现为肿瘤球体启动能力、耐药性和肿瘤复发的增加。综上所述，我们确定了一个利用CD44s激活ZEB1表达的自我实施反馈环。这使得肿瘤细胞的干细胞不受外部刺激的影响，因为ZEB1下调了ESRP1，进一步促进了CD44s异构体的合成。
Invasion and metastasis of carcinomas are often activated by induction of aberrant epithelial-mesenchymal transition (EMT). This is mainly driven by the transcription factor ZEB1, promoting tumor-initiating capacity correlated with increased expression of the putative stem cell marker CD44. However, the direct link between ZEB1, CD44 and tumourigenesis is still enigmatic. Remarkably, EMT-induced repression of ESRP1 controls alternative splicing of CD44, causing a shift in the expression from the variant CD44v to the standard CD44s isoform. We analyzed whether CD44 and ZEB1 regulate each other and show that ZEB1 controls CD44s splicing by repression of ESRP1 in breast and pancreatic cancer. Intriguingly, CD44s itself activates the expression of ZEB1, resulting in a self-sustaining ZEB1 and CD44s expression. Activation of this novel CD44s-ZEB1 regulatory loop has functional impact on tumor cells, as evident by increased tumor-sphere initiation capacity, drug-resistance and tumor recurrence. In summary, we identified a self-enforcing feedback loop that employs CD44s to activate ZEB1 expression. This renders tumor cell stemness independent of external stimuli, as ZEB1 downregulates ESRP1, further promoting CD44s isoform synthesis.