Notch receptor inhibition reveals the importance of cyclin D1 and Wnt signaling in invasive esophageal squamous cell carcinoma.
Notch receptor inhibition reveals the importance of cyclin D1 and Wnt signaling in invasive esophageal squamous cell carcinoma.
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发表时间：
2012
影响因子：
5.3
通讯作者：
S. Naganuma;Kelly A. Whelan;Mitsuteru Natsuizaka;S. Kagawa;H. Kinugasa;Sanders Chang;Harry E Subramanian;Ben Rhoades;S. Ohashi;H. Itoh;M. Herlyn;J. Diehl;P. Gimotty;Andres J Klein-Szanto;H. Nakagawa
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作者：
S. Naganuma;Kelly A. Whelan;Mitsuteru Natsuizaka;S. Kagawa;H. Kinugasa;Sanders Chang;Harry E Subramanian;Ben Rhoades;S. Ohashi;H. Itoh;M. Herlyn;J. Diehl;P. Gimotty;Andres J Klein-Szanto;H. Nakagawa
食管鳞癌(ESCC)是最具侵袭性的鳞状细胞癌之一。食管鳞癌中常见的基因损伤包括p53突变和EGFR过表达，这两种损伤都与Notch信号的负调控有关。此外，细胞周期蛋白D1在食管鳞癌中高表达，并可通过EGFR、Notch和Wnt信号被激活。为了阐明这些遗传损伤在ESCC的发展和进展过程中可能如何相互作用，我们在器官型3D培养(OTC)中测试了一组基因工程的人类食道细胞(角质形成细胞)，OTC是人类组织工程的一种形式。在培养和小鼠中，Notch信号被显性负性主脑样蛋白1(DNMAML1)抑制，DNMAML1是一种遗传的泛Notch抑制剂。采用4-硝基喹啉-1-氧化物诱发DNMAML1小鼠口腔食道癌模型。在OTC和DNMAML1小鼠身上总结了原代人ESCC的高侵袭性特征。在非处方药中，细胞周期蛋白D1过表达导致鳞状细胞增生。EGFR过表达和突变型P53共同导致肿瘤转化和侵袭性生长。有趣的是，细胞增殖似乎在致力于鳞状细胞分化和侵袭间质的细胞之间受到不同的调控。侵袭性细胞表现出非Notch依赖性的细胞周期蛋白D1和Wnt信号的激活。在口腔-食道鳞状上皮内，Notch信号调节鳞状细胞的分化以维持上皮的完整性，因此可能通过阻止促进肿瘤的炎症微环境的发展而起到肿瘤抑制的作用。
Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive forms of squamous cell carcinomas. Common genetic lesions in ESCC include p53 mutations and EGFR overexpression, both of which have been implicated in negative regulation of Notch signaling. In addition, cyclin D1 is overexpressed in ESCC and can be activated via EGFR, Notch and Wnt signaling. To elucidate how these genetic lesions may interact during the development and progression of ESCC, we tested a panel of genetically engineered human esophageal cells (keratinocytes) in organotypic 3D culture (OTC), a form of human tissue engineering. Notch signaling was suppressed in culture and mice by dominant negative Mastermind-like1 (DNMAML1), a genetic pan-Notch inhibitor. DNMAML1 mice were subjected to 4-Nitroquinoline 1-oxide-induced oral-esophageal carcinogenesis. Highly invasive characteristics of primary human ESCC were recapitulated in OTC as well as DNMAML1 mice. In OTC, cyclin D1 overexpression induced squamous hyperplasia. Concurrent EGFR overexpression and mutant p53 resulted in transformation and invasive growth. Interestingly, cell proliferation appeared to be regulated differentially between those committed to squamous-cell differentiation and those invading into the stroma. Invasive cells exhibited Notch-independent activation of cyclin D1 and Wnt signaling. Within the oral-esophageal squamous epithelia, Notch signaling regulated squamous-cell differentiation to maintain epithelial integrity, and thus may act as a tumor suppressor by preventing the development of a tumor-promoting inflammatory microenvironment.