Tumor and Stem Cell Biology ANOTCH 3-MediatedSquamousCell DifferentiationProgram Limits Expansion of EMT-Competent Cells That Express the ZEB Transcription Factors
Tumor and Stem Cell Biology ANOTCH 3-MediatedSquamousCell DifferentiationProgram Limits Expansion of EMT-Competent Cells That Express the ZEB Transcription Factors
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发表时间：
2011
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通讯作者：
S. Ohashi;Mitsuteru Natsuizaka;S. Naganuma;S. Kagawa;Sotai Kimura;H. Itoh;Ross A. Kalman;M. Nakagawa;D. Darling;D. Basu;P. Gimotty;Andres J Klein-Szanto;J. Diehl;M. Herlyn;H. Nakagawa
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作者：
S. Ohashi;Mitsuteru Natsuizaka;S. Naganuma;S. Kagawa;Sotai Kimura;H. Itoh;Ross A. Kalman;M. Nakagawa;D. Darling;D. Basu;P. Gimotty;Andres J Klein-Szanto;J. Diehl;M. Herlyn;H. Nakagawa
锌指E盒结合（ZEB）蛋白ZEB 1和ZEB 2是TGF β介导的衰老、上皮细胞向间充质细胞转化（EMT）和癌症干细胞功能中必需的转录因子。ZEBs受miR-200 microRNA家族成员的负调控，但在侵袭性生长过程中表达ZEBs的肿瘤细胞是如何出现的仍不清楚。在这里，我们报告说，NOTCH 3介导的信号阻止了一个独特的ZEB表达细胞亚群的扩增。ZEB表达与人食管细胞缺乏进行NOTCH 3介导的鳞状分化的细胞能力有关。显性负性母细胞样蛋白1（DNMAML 1）对Notch介导的转录活性的遗传抑制阻止了鳞状分化和Notch靶基因（包括NOTCH 3）的诱导。此外，DNMAML 1富集的EMT感受态细胞在裸鼠中表现出强烈的ZEB上调，miR-200家族下调，以及增强的锚定非依赖性生长和肿瘤形成。RNA干扰实验表明，ZEBs参与锚定独立的集落形成，入侵，和TGF-β介导的EMT。在器官型三维培养（一种人类组织工程形式）中，DNMAML 1抑制Notch后，重现了侵袭性生长和受损的鳞状分化。总之，我们的研究结果表明，NOTCH 3是限制ZEB表达细胞扩增的关键因素，为Notch信号传导在食管鳞癌细胞命运调控和疾病进展中的作用提供了新的机制见解。Cancer Res; 71（21）; 6836-47. 2011年AACR。
Zinc finger E-box–binding (ZEB) proteins ZEB1 and ZEB2 are transcription factors essential in TGFb–mediated senescence, epithelial-to-mesenchymal transition (EMT), and cancer stem cell functions. ZEBs are negatively regulated bymembers of themiR-200microRNA family, but precisely how tumor cells expressing ZEBs emerge during invasive growth remains unknown. Here, we report that NOTCH3-mediated signaling prevents expansion of a unique subset of ZEB-expressing cells. ZEB expression was associated with the lack of cellular capability of undergoing NOTCH3-mediated squamous differentiation in human esophageal cells. Genetic inhibition of the Notch-mediated transcriptional activity by dominant-negative Mastermind-like 1 (DNMAML1) prevented squamous differentiation and induction of Notch target genes including NOTCH3. Moreover, DNMAML1-enriched EMT-competent cells exhibited robust upregulation of ZEBs, downregulation of the miR-200 family, and enhanced anchorage-independent growth and tumor formation in nude mice. RNA interference experiments suggested the involvement of ZEBs in anchorage-independent colony formation, invasion, and TGF-b–mediated EMT. Invasive growth and impaired squamous differentiation were recapitulated upon Notch inhibition by DNMAML1 in organotypic three-dimensional culture, a form of human tissue engineering. Together, our findings indicate that NOTCH3 is a key factor limiting the expansion of ZEBexpressing cells, providing novel mechanistic insights into the role of Notch signaling in the cell fate regulation and disease progression of esophageal squamous cancers. Cancer Res; 71(21); 6836–47. 2011 AACR.