The activated Notch1 signal pathway is associated with gastric cancer progression through cyclooxygenase-2
Journal
Cancer Research
Journal Volume
69
Journal Issue
12
Pages
5039-5048
Date Issued
2009
Abstract
Gastric carcinoma is one of the most common cancers and lethal malignancies worldwide. Thus far, the regulatory mechanisms of its aggressiveness are still poorly understood. To understand the pathogenesis and to develop new therapeutic strategies, it is essential to dissect the molecular mechanisms that regulate progression of gastric cancer. Herein, we sought to address whether Notch1 signal pathway is involved in the control of progression in gastric cancer. We found that expression of Notch ligand Jagged1 was correlated with aggressiveness of human gastric cancer. Patients with Jagged1 expression in gastric cancer tissues had a poor survival rate compared with those without Jagged1 expression. The Notch1 receptor intracellular domain (N1IC), the activated form of Notch1 receptor, promoted the colony-forming ability and xenografted tumor growth of human stomach adenocarcinoma SC-M1 cells. Migration and invasion abilities of SC-M1 cells were enhanced by N1IC. Furthermore, N1IC and C promoter-binding factor 1 (CBF1) bound to cyclooxygenase-2 (COX-2) promoter and elevated COX-2 expression in SC-M1 cells through a CBF1-dependent manner. The colony-forming, migration, and invasion abilities enhanced by N1IC were suppressed in SC-M1 cells after treatment with the COX-2 inhibitor NS-398 or knockdown of COX-2. These cellular processes inhibited by Notch1 knockdown were restored by prostaglandin E2 or exogenous COX-2. Taken together, these results suggest that activation of Notch1 signal pathway promotes progression of gastric cancer, at least in part through COX-2. ?2009 American Association for Cancer Research.
SDGs
Other Subjects
binding protein; C promoter binding factor 1; cyclooxygenase 2; Jagged1; n (2 cyclohexyloxy 4 nitrophenyl)methanesulfonamide; Notch1 receptor; prostaglandin E2; unclassified drug; adult; aged; animal cell; animal experiment; animal model; article; cancer growth; cancer invasion; cancer survival; cancer tissue; cell migration; colony forming unit; controlled study; correlation analysis; female; human; human cell; human tissue; major clinical study; male; mouse; nonhuman; priority journal; protein binding; protein domain; protein expression; protein protein interaction; signal transduction; stomach adenocarcinoma; stomach cancer; tumor xenograft; Adenocarcinoma; Aged; Base Sequence; Calcium-Binding Proteins; Cell Line, Tumor; Cyclooxygenase 2; Disease Progression; DNA Primers; Female; Humans; Intercellular Signaling Peptides and Proteins; Male; Membrane Proteins; Middle Aged; Neoplasm Invasiveness; Neoplasm Metastasis; Polymerase Chain Reaction; Promoter Regions, Genetic; Receptor, Notch1; Signal Transduction; Stomach Neoplasms
Type
journal article