The identification of the factors which enhance EMT in PanIN and the establishment of therapeutic approach to induce pancreatic carcinoma differentiation
| Project/Area Number |
17390213
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | Tohoku University |
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Principal Investigator |
SHIMOSEGAWA Tooru Tohoku University, Tohoku University Graduate School of Medicine, Professor (90226275)
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| Co-Investigator(Kenkyū-buntansha) |
SATOH Kennichi Tohoku University Hospital, 病院, Assistant progessor (10282055)
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| Project Period (FY) |
2005 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥15,850,000 (Direct Cost: ¥15,400,000、Indirect Cost: ¥450,000)
Fiscal Year 2007: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2006: ¥5,100,000 (Direct Cost: ¥5,100,000)
Fiscal Year 2005: ¥8,800,000 (Direct Cost: ¥8,800,000)
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| Keywords | Pancreatic cancer / PanIN / EMT |
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| Research Abstract |
Firstly, we investigate whether BMP4 would induce epithelial to mesenchymal transition (EMT) in pancreatic cancer, in order to explore the key factor which facilitates to induce EMT in early stage of pancreatic carcinogenesis. BMP4-treated Panc-1 cells showed loose cell contacts and scattered fibroblast like appearance along with E-cadherin down-regulation, Vimentin up-regulation and enhanced cell migration, which are characteristic of EMT. BMP4 treatment also induced homeobox gene MSX2 was markedly induced by BMP4 through ERK and p38 MAPK pathways collaboratively with Smad signaling pathway. The repression of E-cadherin, induction of Vimentin and enhanced cell migration were disappeared when siRNA-based MSX2 down-regulated pancreatic cancer cells were treated with BMP4. These findings indicate that BMP4 may be involved in pancreatic carcinoma development through the promotion of EMT and that MSX2 is indispensable to this process.
We then tested whether MSX2 itself could induce EMT in pancreatic carcinoma cells. BxPC3 cells stably expressing MSX2 showed a flattened and scattered morphology accompanied by a change in localization of E-cadherin and β-catenin from membrane to cytoplasm. Cell proliferation rate, cell migration and anchorage independent cell growth were enhanced in MSX2 expressing cells. MSX2 expressing cells also show significantly more frequent liver metastases and disseminations in nude mice than did control cells when cells were injected into pancreas. Immunohistochemistry revealed that MSX2 was frequently expressed and increased expression of MSX2 was significantly correlated with higher tumor grade, vascular invasion. These data indicate that MSX2 is one of the factors which contribute to induce EMT in pancreatic carcinoma development.
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Report
(4 results)
Research Products
(20 results)
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[Journal Article] Up-Regulation of MSX2 Enhances the Malignant Phenotype and Is Associated with Twist 1 Expression in Human Pancreatic Cancer Cells.2008
Author(s)
Satoh K, Hamada S, Kimura K, Kanno A, Hirota M, Umino J, Fujibuchi W, MasamuneA, Tanaka N, Miura K, Egawa S, Motoi F, Unno M, Vonderhaar BK, Shimosegawa T.
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Journal Title
Am J Pathol 172
Pages: 926-939
Description
「研究成果報告書概要(和文)」より
Related Report
Peer Reviewed
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[Journal Article] Up-Regulation of MSX2 Enhances the Malignant Phenotype and Is Associated with Twist 1 Expression in Human Pancreatic Cancer Cells2008
Author(s)
Satoh K, Hamada S, Kimura K, Kanno A, Hirota M, Umino J, Fujibuchi W, Masamune A, Tanaka N, Miura K, Egawa S, Motoi F, Unno M, Vonderhaar BK, Shimosegawa T.
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Journal Title
Am J Pathol 172
Pages: 926-939
Description
「研究成果報告書概要(欧文)」より
Related Report
-
[Journal Article] Up-Regulation of MSX2 Enhances the Malignant Phenotype and Is Associated with Twist 1 Expression in Human Pancreatic Cancer Cells.2008
Author(s)
Satoh K, Hamada S, Kimura K, Kanno A, Hirota M, Umino J, Fujiuchi W, MasamuneA, Tanaka N, Miura K, Egawa S, Motoi F, Unno M, Vonderhaar BK, Shimosegawa T.
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Journal Title
Am J Pathol 172
Pages: 926-939
Related Report
Peer Reviewed
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[Journal Article] Mutations in the serine protease inhibitor Kazal Type 1 (SPINK1) gene in Japanese patients with pancreatitis2005
Author(s)
Kume K, Masamune A, Mizutamari H, Kaneko K, Kikuta K, Satoh M.Satoh K, Kimura K, Suzuki N, Nagasaki Y, Horii A, Shimosegawa T.
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Journal Title
Pnacreatology 5
Pages: 354-360
Related Report
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