Notch receptor inhibition reveals the importance of cyclin D1 and Wnt signaling in invasive esophageal squamous cell carcinoma

American Journal of Cancer Research

Shinya Ohashi¹  Hiroshi Nakagawa¹  Ben Rhoades¹  Hiroshi Itoh¹  Kelly A Whelan¹  J Alan Diehl¹  Phyllis A Gimotty¹  Andres J Klein-Szanto¹  Seiji Naganuma¹  Mitsuteru Natsuizaka¹  Shingo Kagawa¹  Harry Subramanian¹  Hideaki Kinugasa¹  Sanders Chang¹  Meenhard Herlyn¹ 

关键词: Esophageal squamous cell carcinoma;    organotypic 3D culture;    EGFR;    P53;    cyclin D1;    Wnt;    Notch;    squamous-cell differentiation;    invasion;    4-Nitroquinoline 1-oxide;   

DOI  :  

学科分类：肿瘤学

来源: e-Century Publishing Corporation

【 摘 要 】

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.

【 授权许可】

Unknown