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Published on: January 12, 2020
Notch2-induced COX-2 expression enhancing gastric cancer progression
Yun-Chien Tseng1, Yu-Hui Tsai, Min-Jen Tseng
1Department of Anatomy and Cell Biology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
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.
Insights
The Notch2-COX-2 signaling axis promotes gastric cancer progression by enhancing cell proliferation and invasion. Inhibiting this pathway could offer new therapeutic strategies for stomach adenocarcinoma.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Gastric carcinoma is a leading cause of cancer mortality globally, with mechanisms of aggressiveness poorly understood.
- The Notch signaling pathway, including Notch receptors 1-4, plays complex roles in tumorigenesis, acting as either an oncogene or tumor suppressor.
- Previous research linked activated Notch1 to gastric cancer progression via cyclooxygenase-2 (COX-2).
Purpose of the Study:
- To investigate the role of the Notch2 signaling pathway in gastric cancer progression.
- To determine if Notch2 influences gastric cancer cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT).
- To elucidate the molecular mechanism linking Notch2 to gastric cancer progression, specifically its interaction with COX-2.
Main Methods:
- Utilized human stomach adenocarcinoma cell lines (SC-M1, AGS, AZ521) with constitutive expression of Notch2 intracellular domain (N2IC) or Notch2 knockdown.
- Assessed cell proliferation, colony formation, migration, invasion, and wound-healing assays.
- Investigated EMT markers, Notch2 binding to the COX-2 promoter, COX-2 expression, and the effects of COX-2 inhibition (NS-398) or prostaglandin E2 (PGE2).
Main Results:
- Constitutive N2IC expression enhanced SC-M1 cell proliferation, migration, invasion, and tumor growth.
- Notch2 knockdown inhibited cancer progression in SC-M1, AGS, and AZ521 cells.
- N2IC induced EMT and upregulated COX-2 expression via a CBF1-dependent mechanism.
- COX-2 inhibition or knockdown suppressed N2IC-mediated tumor progression, while exogenous COX-2 or PGE2 reversed Notch2 knockdown effects.
Conclusions:
- The Notch2 signaling pathway, through its interaction with COX-2, significantly contributes to gastric cancer progression.
- The Notch2-COX-2 axis promotes gastric cancer cell proliferation, invasion, and EMT.
- Targeting the Notch2-COX-2 pathway presents a potential therapeutic strategy for gastric cancer.
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