Gastric
carcinoma is one of the most common and mortal types of
malignancy worldwide. To date, the mechanisms controlling its aggressiveness are not yet fully understood. Notch signal pathway can function as either an oncogene or a
tumor suppressor in
tumorigenesis. Four members (Notch1-4) of
Notch receptors were found in mammals and each exhibits distinct roles in
tumor progression. Previous study showed that the activated
Notch1 receptor promoted
gastric cancer progression through
cyclooxygenase-2 (COX-2). This study addressed whether Notch2 signal pathway is also involved in
gastric cancer progression. Constitutive expression of Notch2 intracellular domain (N2IC), the activated form of
Notch2 receptor, promoted both cell proliferation and xenografted
tumor growth of human stomach
adenocarcinoma SC-M1 cells. The colony formation, migration, invasion, and wound-healing abilities of SC-M1 cells were enhanced by N2IC expression, whereas these abilities were suppressed by Notch2 knockdown. Similarly, Notch2 knockdown inhibited
cancer progressions of AGS and AZ521
gastric cancer cells. Expression of N2IC also caused epithelial-mesenchymal transition in SC-M1 cells. Furthermore, N2IC bound to COX-2 promoter and induced COX-2 expression through a CBF1-dependent manner in SC-M1 cells. The ability of N2IC to enhance
tumor progression in SC-M1 cells was suppressed by knockdown of COX-2 or treatment with
NS-398, a
COX-2 inhibitor. Moreover, the suppression of
tumor progression by Notch2 knockdown in SC-M1 cells was reversed by exogenous COX-2 or its major enzymatic product
PGE(2) . Taken together, this study is the first to demonstrate that the Notch2-COX-2 signaling axis plays an important role in controlling
gastric cancer progression.