Notch1 directly induced CD133 expression in human diffuse type gastric cancers

• Published in: Oncotarget Vol. 7; no. 35; pp. 56598 - 56607
• Main Authors: Konishi, Hidetomo, Asano, Naoki, Imatani, Akira, Kimura, Osamu, Kondo, Yutaka, Jin, Xiaoyi, Kanno, Takeshi, Hatta, Waku, Ara, Nobuyuki, Asanuma, Kiyotaka, Koike, Tomoyuki, Shimosegawa, Tooru
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 30.08.2016
• Subjects: AC133 Antigen - genetics; AC133 Antigen - metabolism; Binding Sites; Cell Adhesion; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Disease Progression; Gene Expression Regulation, Neoplastic; Humans; Immunoglobulin J Recombination Signal Sequence-Binding Protein - genetics; Immunoglobulin J Recombination Signal Sequence-Binding Protein - metabolism; Neoplastic Stem Cells - cytology; Phenotype; Promoter Regions, Genetic; Receptor, Notch1 - genetics; Receptor, Notch1 - metabolism; Research Paper; Signal Transduction; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism; Transfection; RBP-J kappa; cancer stem cell; gastric cancer; Notch; CD133
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.10967

CD133 is considered as a stem-like cell marker in some cancers including gastric cancers, and Notch1 signaling is known to play an important role in the maintenance and differentiation of stem-like cells. We aimed to investigate whether Notch1 signaling contributes to the carcinogenesis of gastric cancers and CD133 induction. CD133 expression was detected in 51.4% of diffuse type gastric cancers while it was not detected in intestinal type gastric cancers. Similarly, only poorly-differentiated gastric cancer cell lines expressed CD133 and activated-Notch1. Inhibiting Notch1 signaling resulted in decreased CD133 expression, side population cells, cell proliferation and anchorage independent cell growth. Chromatin immunoprecipitation suggested that this Notch1 dependent regulation of CD133 was caused by direct binding of activated-Notch1 to the RBP-Jκ binding site in the 5' promoter region of CD133 gene. In addition, knocking down RBP-Jκ reduced CD133 induction in activated-Notch1 transfected cells. These findings suggested that Notch1 signaling plays an important role in the maintenance of the cancer stem-like phenotype in diffuse type gastric cancer through an RBP-Jκ dependent pathway and that inhibiting Notch1 signaling could be an effective therapy against CD133 positive diffuse type gastric cancers.