Cooperation of Wnt signaling and COX-2 pathway in gastric carcinogenesis
| Project/Area Number |
17390114
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Experimental pathology
|
|---|
| Research Institution | Kanazawa University |
|---|
Principal Investigator |
OSHIMA Masanobu Kanazawa University, Cancer Research Instituge, Professor, がん研究所, 教授 (40324610)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
OSHIMA Hiroko Kanazawa University, Cancer Research Institute, Assistant Professor, がん研究所, 助手 (80362515)
|
|---|
| Project Period (FY) |
2005 – 2006
|
| Project Status |
Completed (Fiscal Year 2006)
|
| Budget Amount *help |
¥14,600,000 (Direct Cost: ¥14,600,000)
Fiscal Year 2006: ¥6,300,000 (Direct Cost: ¥6,300,000)
Fiscal Year 2005: ¥8,300,000 (Direct Cost: ¥8,300,000)
|
|---|
| Keywords | Gastric cancer / Inflammation / COX-2 / Wnt / Mouse model |
|---|
| Research Abstract |
Accumulating evidence indicates that the Wnt signaling as well as prostaglandin E_2 (PGE_2), a downstream product of cyclooxygenase 2 (COX-2), plays a key role in gastric tumorigenesis. However, the molecular mechanism remains poorly understood how the Wnt and PGE_2 pathways contribute to gastric tumorigenesis. To investigate their roles in gastric cancer, we have generated transgenic mice activating both pathways in the gastric epithelial cells, and examined their phenotypes. First, we constructed K19-C2mE mice that expressed COX-2 and mPGES-1 in the gastric mucosa using the keratin 19 (K19) promoter. mPGES-1 is a PGE_2 converting enzyme induced simultaneously with COX-2 in a variety of cancers. K19-C2mE mice showed mucous cell metaplasia and hyperplasia in the glandular stomach with heavy macrophage accumulation. Activation of mucosal macrophages and inflammatory response were responsible for metaplastic hyperplasia in K19-C2mE mice. We next constructed K19-Wntl transgenic mice expressing Wntl in the gastric mucosa under the control of K19 promoter. K19-Wntl mice had a significant suppression of epithelial differentiation, and developed small preneoplastic lesions consisting of undifferentiated epithelial cells with macrophage accumulation. However, K19-Wntl mice did not develop gastric tumors. We then crossed K19-Wnt1 mice with K19-C2mE to obtain K19-Wnt1/C2mE compound transgenic mice. Importantly, increase of PGE_2 through induction of COX-2 and mPGES-1 in the K19-Wnt1 mice converted the preneoplastic lesions into malignant gastric tumors. These results indicate that simultaneous activation of both Wnt and PGE_2 pathways causes malignant gastric tumors. Accordingly, K19-Wntl/C2mE mouse model is a useful, tool to study the genetic mechanism of gastric carcinogenesis through activation of the Wnt and PGE_2 pathways.
|
Report
(3 results)
Research Products
(20 results)
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
[Journal Article] ROCK-I regulates closure of the eyelids and ventral body wall by inducing assembly of actomyosin bundles.2005
Author(s)
Shimizu, Y., Thumkeo, D., Keel, J., Ishizaki, T., Oshima, H., Oshima, M., Noda, Y., Matsumura, F., Taketo, M.M., Narumiya, S.
-
Journal Title
J.Cell Biol. 168
Pages: 941-953
Related Report
-
-
-
