Notch4 Signaling Induces a Mesenchymal-Epithelial-like Transition in Melanoma Cells to Suppress Malignant Behaviors.
Notch4 Signaling Induces a Mesenchymal-Epithelial-like Transition in Melanoma Cells to Suppress Malignant Behaviors.
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DOI：
10.1158/0008-5472.can-15-1722
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发表时间：
2016-04-01
期刊：
影响因子：
11.2
通讯作者：
Schaider H
中科院分区：
文献类型：
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作者：
Bonyadi Rad E;Hammerlindl H;Wels C;Popper U;Ravindran Menon D;Breiteneder H;Kitzwoegerer M;Hafner C;Herlyn M;Bergler H;Schaider H
Notch信号的作用是上下文依赖的，并且已经描述了致癌和肿瘤抑制功能。Notch信号在黑色素瘤中被认为是致癌的，但是在这种恶性肿瘤中测试Notch抑制的临床试验尚未证明是成功的。在这里，我们报道了黑色素瘤细胞中组成型活性细胞内结构域Notch4 （N4ICD）的表达触发了从间充质样亲代表型到上皮样表型的转换。上皮样形态伴随着侵袭性、迁移性和增殖性的显著降低，同时伴有上皮-间质转化标记Snail2 （SNAI2）、Twist1、vimentin （VIM）和MMP2的下调以及E-cadherin （CDH1）的重表达。n4icd诱导的表型转换也导致体内肿瘤生长显著降低。免疫组化分析原发性人黑色素瘤和皮肤转移瘤显示Notch4与E-cadherin表达有显著相关性。通过EMSA和荧光素酶检测，我们发现N4ICD诱导了转录因子Hey1和Hey2的表达，这两个转录因子直接结合到Snail2和Twist1的启动子区域，并抑制了基因的转录。综上所述，我们的研究结果表明Notch4在黑色素瘤中作为肿瘤抑制因子的作用，揭示了在这种情况下观察到的Notch抑制剂临床疗效差的潜在解释。
The effects of Notch signaling are context-dependent and both oncogenic and tumor-suppressive functions have been described. Notch signaling in melanoma is considered oncogenic, but clinical trials testing Notch inhibition in this malignancy have not proved successful. Here, we report that expression of the constitutively active intracellular domain of Notch4 (N4ICD) in melanoma cells triggered a switch from a mesenchymal-like parental phenotype to an epithelial-like phenotype. The epithelial-like morphology was accompanied by strongly reduced invasive, migratory, and proliferative properties concomitant with the downregulation of epithelial–mesenchymal transition markers Snail2 (SNAI2), Twist1, vimentin (VIM), and MMP2 and the reexpression of E-cadherin (CDH1). The N4ICD-induced phenotypic switch also resulted in significantly reduced tumor growth in vivo. Immunohistochemical analysis of primary human melanomas and cutaneous metastases revealed a significant correlation between Notch4 and E-cadherin expression. Mechanistically, we demonstrate that N4ICD induced the expression of the transcription factors Hey1 and Hey2, which bound directly to the promoter regions of Snail2 and Twist1 and repressed gene transcription, as determined by EMSA and luciferase assays. Taken together, our findings indicate a role for Notch4 as a tumor suppressor in melanoma, uncovering a potential explanation for the poor clinical efficacy of Notch inhibitors observed in this setting.