Interplay between Notch1 and Notch3 promotes EMT and tumor initiation in squamous cell carcinoma.
Interplay between Notch1 and Notch3 promotes EMT and tumor initiation in squamous cell carcinoma.
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Notch1和Notch3之间的相互作用促进了鳞状细胞癌的EMT和肿瘤的发生。
DOI：
10.1038/s41467-017-01500-9
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发表时间：
2017-11-24
影响因子：
16.6
通讯作者：
Nakagawa H
中科院分区：
文献类型：
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作者：
Natsuizaka M;Whelan KA;Kagawa S;Tanaka K;Giroux V;Chandramouleeswaran PM;Long A;Sahu V;Darling DS;Que J;Yang Y;Katz JP;Wileyto EP;Basu D;Kita Y;Natsugoe S;Naganuma S;Klein-Szanto AJ;Diehl JA;Bass AJ;Wong KK;Rustgi AK;Nakagawa H
NOTCH1反式激活Notch3以驱动复层鳞状上皮的末端分化。NOTCH1和其他Notch受体类似物协同作用，在鳞状细胞癌(SCCs)中发挥肿瘤抑制作用。然而，Notch1可以被随机激活以促进小鼠鳞状细胞癌模型的癌变。当异位表达时，激活形式的Notch1促进异种移植瘤的生长。在这里，我们证明了Notch1的激活和上皮-间充质转化共同促进了鳞状细胞癌肿瘤的启动，肿瘤微环境中存在转化生长因子-β。我们发现转化生长因子β激活转录因子ZEB1抑制Notch3，从而限制末端分化。同时，转化生长因子β驱动Notch1介导的内皮细胞转化产生高表达CD44的肿瘤起始细胞。此外，Notch1在侵袭性肿瘤前沿的一小部分SCC细胞中被激活，并预示着食道SCC的不良预后，从而揭示了Notch1在SCC中促进肿瘤发生的作用。Notch受体在癌症中可以发挥不同的作用。在这篇论文中，作者揭示了Notch1的激活和EMT促进了鳞状细胞癌的肿瘤起始和癌细胞异质性，而ZEB1对Notch3的抑制限制了Notch1诱导的分化，允许Notch1介导的EMT。
Notch1 transactivates Notch3 to drive terminal differentiation in stratified squamous epithelia. Notch1 and other Notch receptor paralogs cooperate to act as a tumor suppressor in squamous cell carcinomas (SCCs). However, Notch1 can be stochastically activated to promote carcinogenesis in murine models of SCC. Activated form of Notch1 promotes xenograft tumor growth when expressed ectopically. Here, we demonstrate that Notch1 activation and epithelial–mesenchymal transition (EMT) are coupled to promote SCC tumor initiation in concert with transforming growth factor (TGF)-β present in the tumor microenvironment. We find that TGFβ activates the transcription factor ZEB1 to repress Notch3, thereby limiting terminal differentiation. Concurrently, TGFβ drives Notch1-mediated EMT to generate tumor initiating cells characterized by high CD44 expression. Moreover, Notch1 is activated in a small subset of SCC cells at the invasive tumor front and predicts for poor prognosis of esophageal SCC, shedding light upon the tumor promoting oncogenic aspect of Notch1 in SCC. Notch receptors can exert different roles in cancer. In this manuscript, the authors reveal that Notch1 activation and EMT promote tumor initiation and cancer cell heterogeneity in squamous cell carcinoma, while the repression of Notch3 by ZEB1 limits Notch1-induced differentiation, permitting Notch1-mediated EMT.
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