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 E(2) 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.
Highlights
Notch signal pathway is involved in several cellular processes, such as proliferation, differentiation, apoptosis, cell fate decision, and maintenance of stem cells [1,2,3]
To study whether Notch1 signal pathway is involved in the progression of human gastric cancer, immunohistochemical stains of Notch1 receptor and Jagged1 were performed on gastric cancer tissues to examine their clinical relevance
We examined DNA-binding ability of these proteins on COX-2 promoter by Chromatin immunoprecipitation (ChIP) assay using anti-IgG, anti-Notch1 COOH terminus, and anti-C promoter–binding factor 1 (CBF1) antibodies in SC-M1/HA-Notch1 receptor intracellular domain (N1IC) cells
Summary
Notch signal pathway is involved in several cellular processes, such as proliferation, differentiation, apoptosis, cell fate decision, and maintenance of stem cells [1,2,3]. It plays an important role in the control of tumorigenesis [1,2,3]. In the canonical Notch signal pathway, Notch receptor is activated and cleaved to release and translocate its intracellular domain into the nucleus after ligand binding. The cleaved Notch receptor intracellular domain regulates its downstream target genes via both C promoter–binding factor 1 (CBF1; called RBP-Jκ)–dependent and –independent pathways [3]
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