Notch1 directly induced CD133 expression in human diffuse type gastric cancers.

Hidetomo Konishi,Yutaka Kondo,Kiyotaka Asanuma,Xiaoyi Jin,Osamu Kimura,Waku Hatta,Nobuyuki Ara,Tooru Shimosegawa,Tomoyuki Koike,Akira Imatani,Takeshi Kanno,Naoki Asano

doi:10.18632/oncotarget.10967

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.

Highlights

Gastric cancer is the fourth most common cancer in the world [1], and can be classified into two histological groups: intestinal type and diffuse type [2,3,4]
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
Among the 74 specimens we evaluated, CD133 was expressed in 19/37 diffuse type gastric cancers (51.4%), www.impactjournals.com/oncotarget whereas it was not expressed in any of the intestinal type gastric cancers (0/37; 0%)

Summary

Introduction

Gastric cancer is the fourth most common cancer in the world [1], and can be classified into two histological groups: intestinal type and diffuse type [2,3,4]. Diffuse type gastric cancers are considered to arise from an abnormality of stem-like cells in a proliferating zone in the isthmus of oxyntic glands [3]. These diffuse type gastric cancers progress more rapidly and cause metastasis leading to poor prognosis [6]. Notch signaling has been reported to be involved in the maintenance and differentiation of stem-like cells [7, 8]. It is involved in the development of adenomas and cancers [9, 10]

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