Notch1 is a 5-fluorouracil resistant and poor survival marker in human esophagus squamous cell carcinomas

• Published in: PloS one Vol. 8; no. 2; p. e56141
• Main Authors: Liu, Jian, Fan, Huijie, Ma, Yuanyuan, Liang, Dongming, Huang, Ruixia, Wang, Junsheng, Zhou, Fuyou, Kan, Quancheng, Ming, Liang, Li, Huixiang, Giercksky, Karl-Erik, Nesland, Jahn Martin, Suo, Zhenhe
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 07.02.2013; Public Library of Science (PLoS)
• Subjects: 5-Fluorouracil; Analysis; Basal cells; Biology; Biomarkers, Tumor - genetics; Biotechnology; Cancer; Cancer therapies; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - pathology; Cell cycle; Cell differentiation; Cell fate; Cell growth; Cell Hypoxia - drug effects; Cell Hypoxia - genetics; Cell Line, Tumor; Cell proliferation; Cell survival; Cell Transformation, Viral; Clinical medicine; Colorectal cancer; Differentiation (biology); Drug resistance; Drug Resistance, Neoplasm - genetics; Epithelial cells; Epithelial Cells - pathology; Esophageal cancer; Esophageal carcinoma; Esophageal Neoplasms - drug therapy; Esophageal Neoplasms - genetics; Esophageal Neoplasms - pathology; Esophagus; Female; Fluorouracil; Fluorouracil - pharmacology; Fluorouracil - therapeutic use; Follow-Up Studies; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Human papillomavirus; Humans; Hypoxia; Male; Medicine; Metastasis; Notch protein; Notch1 protein; Notch3 protein; Oncology; Pathology; Polymerase chain reaction; Receptor, Notch1 - genetics; Signaling; Squamous cell carcinoma; Stem cells; Studies; Survival; Survival Analysis; Tumor cell lines; Tumorigenesis; Tumors; Viruses; Norway
• DOI: 10.1371/journal.pone.0056141
• ISSN: 1932-6203

Notch signaling involves the processes that govern cell proliferation, cell fate decision, cell differentiation and stem cell maintenance. Due to its fundamental role in stem cells, it has been speculated during the recent years that Notch family may have critical functions in cancer stem cells or cancer cells with a stem cell phenotype, therefore playing an important role in the process of oncogenesis. In this study, expression of Notch family in KYSE70, KYSE140 and KYSE450 squamous esophageal cancer cell lines and virus transformed squamous esophageal epithelial cell line Het-1A was examined by quantitative RT-PCR. Compared to the Het-1A cells, higher levels of Nocth1 and Notch3 expression in the cancer cell lines were identified. Due to the finding that NOTCH3 mainly mediates squamous cell differentiation, NOTCH1 expression was further studied in these cell lines. By Western blot analyses, the KYSE70 cell line which derived from a poorly differentiated tumor highly expressed Notch1, and the Notch1 expression in this cell line was hypoxia inducible, while the KYSE450 cell line which derived from a well differentiated tumor was always negative for Notch1, even in hypoxia. Additional studies demonstrated that the KYSE70 cell line was more 5-FU resistant than the KYSE450 cell line and such 5-FU resistance is correlated to Notch1 expression verified by Notch1 knockdown experiments. In clinical samples, Notch1 protein expression was detected in the basal cells of human esophagus epithelia, and its expression in squamous cell carcinomas was significantly associated with higher pathological grade and shorter overall survival. We conclude that Notch1 expression is associated with cell aggressiveness and 5-FU drug resistance in human esophageal squamous cell carcinoma cell lines in vitro and is significantly associated with a poor survival in human esophageal squamous cell carcinomas.