The activated Notch1 signal pathway is associated with gastric cancer progression through cyclooxygenase-2.
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.
Yeh
Tien-Shun
TS
Department of Anatomy and Cell Biology, National Yang-Ming University, Taipei 112, Taiwan. tsyeh@ym.edu.tw
Wu
Chew-Wun
CW
Hsu
Kai-Wen
KW
Liao
Wan-Jung
WJ
Yang
Min-Chieh
MC
Li
Anna Fen-Yau
AF
Wang
An-Ming
AM
Kuo
Min-Liang
ML
Chi
Chin-Wen
CW
D000230:Adenocarcinoma / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D000368:Aged; D001483:Base Sequence; D002135:Calcium-Binding Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers; D018450:Disease Progression; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D000072100:Jagged-1 Protein; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D051881:Receptor, Notch1 / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*
D002135:Calcium-Binding Proteins; D017931:DNA Primers; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D000072099:Serrate-Jagged Proteins; D051546:Cyclooxygenase 2