The Activated Notch1 Signal Pathway Is Associated with Gastric Cancer Progression through Cyclooxygenase-2
The Activated Notch1 Signal Pathway Is Associated with Gastric Cancer Progression through Cyclooxygenase-2
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DOI：
10.1158/0008-5472.can-08-4021
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发表时间：
2009-06-15
期刊：
影响因子：
11.2
通讯作者：
Chi, Chin-Wen
中科院分区：
文献类型：
--
作者：
Yeh, Tien-Shun;Wu, Chew-Wun;Chi, Chin-Wen
胃癌是世界上最常见的恶性肿瘤之一。到目前为止，其侵略性的调节机制仍然知之甚少。研究胃癌发生发展的分子机制，对于了解胃癌的发病机制和开发新的治疗策略是非常必要的。在此，我们试图解决Notch 1信号通路是否参与胃癌进展的控制。我们发现Notch配体Jagged 1的表达与人胃癌的侵袭性相关。胃癌组织中有Jagged 1表达的患者与无Jagged 1表达的患者相比，生存率较差。Notch 1受体胞内结构域（N1 IC）是Notch 1受体的激活形式，可促进人胃腺癌SC-M1细胞的集落形成能力和移植瘤的生长。N1 IC可增强SC-M1细胞的迁移和侵袭能力。此外，N1 IC和C启动子结合因子1（CBF 1）与环氧化酶-2（考克斯-2）启动子结合，通过CBF 1依赖的方式提高SC-M1细胞中考克斯-2的表达。用考克斯-2抑制剂NS-398或敲低考克斯-2后，SC-M1细胞中N1 IC增强的集落形成、迁移和侵袭能力受到抑制。这些被Notch 1敲低抑制的细胞过程被前列腺素E（2）或外源性考克斯-2恢复。综上所述，这些结果表明，Notch 1信号通路的激活促进胃癌的进展，至少部分通过考克斯-2。[Cancer Res 2009;69（12）：5039-48]
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. [Cancer Res 2009;69(12):5039-48]