Notch2‐induced COX‐2 expression enhancing gastric cancer progression

Abstract

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.

Prognostic values of four Notch receptor mRNA expression in gastric cancer

“…Constitutive expression of Notch2 NICD promoted both cell proliferation and xenografted tumor growth of human gastric adenocarcinoma SC-M1 cells46. Immunohistochemical analysis demonstrated a chemotherapy-associated increase in the intensity of Notch2 staining, indicating a prominent role for Notch2 in chemotherapy resistance of gastric cancer47.…”

Yin Yang 1 is a target of microRNA-34 family and contributes to gastric carcinogenesis

“…Additionally, cells were also seeded and subsequently assessed cell viability by MTT (Sigma-Aldrich) assay as described previously [48]. …”

ERK inhibition enhances TSA-induced gastric cancer cell apoptosis via NF-κB-dependent and Notch-independent mechanism

“…Although dysregulation of Notch signaling has been reported in GC (Tseng et al, 2011), and HDACIs induce Notch signaling in different types of cancer cells (Adler et al, 2008;Schwarz et al, 2011), little is known about effects of HDACIs on Notch signaling in human GC cells. Moreover, previous studies have provided considerable evidence of cross talk among the Notch, NF-κB and ERK1/2 signaling pathways (Kim et al, 2006a(Kim et al, , 2006bManiati et al, 2011;Xu et al, 2011).…”