Notch1 directly induced CD133 expression in human diffuse type gastric cancers

// Hidetomo Konishi 1 , Naoki Asano 1 , Akira Imatani 1 , Osamu Kimura 1 , Yutaka Kondo 1 , Xiaoyi Jin 1 , Takeshi Kanno 1 , Waku Hatta 1 , Nobuyuki Ara 1 , Kiyotaka Asanuma 1 , Tomoyuki Koike 1 , Tooru Shimosegawa 1 1 Division of Gastroenterology, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Miyagi 980-8574, Japan Correspondence to: Akira Imatani, email: aimatani@med.tohoku.ac.jp Keywords: Notch, RBP-J kappa, cancer stem cell, gastric cancer, CD133 Received: June 04, 2016      Accepted: July 19, 2016      Published: July 30, 2016 ABSTRACT 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.