Roles of the activated Notch2 receptor in gastric cancer progression

• Main Authors: Yun-Chien Tseng, 曾芸倩
• Other Authors: Tien-Shun Yeh
• Format: Others
• Language: zh-TW
• Published: 2009
• Online Access: http://ndltd.ncl.edu.tw/handle/7f6645

碩士 === 國立陽明大學 === 解剖暨細胞生物學研究所 === 97 === Gastric carcinoma is one of the most common malignancies worldwide. Diagnosis of the early-stage gastric cancer is difficult, so it always has poor outcome. COX-2 expression is correlated with depth of invasion, lymphatic vessel invasion, lymph node metastasis, and poor prognosis of human gastric carcinoma. In gastric cancer cells with fibroblastoid morphological changes, activation of epithelial to mesenchymal transition (EMT) signaling was suggested to promote motility and invasiveness through decreasing cell-cell adhesion. The activation of Notch signal pathway participates in EMT in development and tumorigenesis. The Notch signaling pathway plays an important role in cell fate determination, differentiation, proliferation, apoptosis. The activated Notch receptor could be oncogenic or tumor suppressive to modulate tumorigenesis. However, the mechanism of gastric carcinoma progression is not clear until now. To study role of Notch2 signaling in tumor progression of SC-M1 cells, Notch2 receptor intracellular domain (N2IC)-expressing cells (SC-M1/myc-N2IC-His) and Notch2-knockdown cells (SC-M1/Notch2i) were established in the present study. We showed that cell proliferation of SC-M1 gastric cancer cells was increased by the expression of N2IC, the activated form of Notch2 receptor. The activated Notch2 receptor raised the colony-forming, migration and invasion abilities of SC-M1 cells. The knockdown of endogenous Notch2 receptor inhibited cell proliferation, colony-forming, migration and invasion abilities. Overexpression of N2IC exhibited fibroblastoid morphological change and knockdown of endogenous Notch2 receptor exhibited cuboidal-like morphological change in SC-M1 cells. Additionally, N2IC increased the expression of COX-2. The fibroblastoid morphological change induced by N2IC was attenuated after treatment with COX-2 inhibitor, NS-398 in SC-M1 cells. NS-398 inhibited colony-forming、migration and invasion abilities enhanced by N2IC. COX-2 knockdown inhibited colony-forming、migration and invasion abilities enhanced by N2IC. Knockdown of Notch2 receptor repressed COX-2 expression. PGE2 restored migration and invasion abilities suppressed by knockdown of endogenous Notch2 receptor in SC-M1 cells. Exogenous COX-2 restores migration and invasion abilities suppressed by knockdown of endogenous Notch2 receptor in SC-M1 cells. We also found that N2IC bound to COX-2 promoter and enhanced the COX-2 promoter activity to regulate the expression of COX-2. Furthermore, N2IC regulated colony-forming, migration and invasion abilities through COX-2. These results suggest that Notch2 signaling is critical for promotion of tumor progression in gastric cancer cells by up-regulating COX-2 expression.