2002 Fiscal Year Final Research Report Summary
Experimental gene therapy employing DUSP6/MKP-3 for pancreatic cancer
| Project/Area Number |
13670161
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Human pathology
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| Research Institution | Tohoku University |
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Principal Investigator |
FURUKAWA Toru Tohoku University, Graduate School of Medicine, Research Associate, 大学院・医学研究科, 助手 (30282122)
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| Project Period (FY) |
2001 – 2002
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| Keywords | DUSP6 / MKP-3 / pancreatic cancer / Tumor suppressor gene / Gene therapy / MAPK / Adenovirus / Apoptosis / LoH |
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| Research Abstract |
The loss of heterozygosity at 12q21 and 12q22-q23.1 is frequently found in primary pancreatic cancers ard DUSP6/MKP-3 gene residing in this region at 12q22 lost its expression in the great majority of pancreatic cancer cell lines. The DUSP6/MKP-3 protein is a dual spcificity phosphatase that dephosphorylates the active form of ERK, making a feed back loop to control ERK activity. Gain-of-function mutations of KRAS2 occur ih the great majority of pancreatic cancer cells, and loss of expression of DUSP6/MKP-3 may synergistically promote constitutive activation of ERK and uncontrolled cell growth. To study loss of the feed back pathway and its impact to pancreatic cancer cell growth, the expression of DUSP6/MKP-3 in primary pancreatic cancer tissues was investigated immunohistochemically ; upregulation in mildly as well as severely dysplasticlin situ carcinoma cells and downregulation in invasive carcinoma, especially that of the poorly differentiated type were found. Adenovirus-mediated reintroduction of DUSP6/MKP-3 into cultured pancreatic cancer cells induced strong expression of recombinant DUSP6/MKP-3 and reductin of phosphorylated ERK in a dose-dependent manner based on the multiplicity of infection and resulted in suppression of cell growth. Moreover, analyses by flow cytometry and immunocytochemistry revealed that the exogenous expression of DUSP6/MKP-3 induced apoptosis. In an experimental gene therapy for xenographted human pancreatic cell tumors in nude mice revealed transient retardation of tumor growth. However, dose and administrative ways should be altered for more efficient therapy result. These results shovv that DUSP6 exerts apparent tumor-suppressive effects, and suggest that DUSP6 is a strong candidate tumor suppressor gene at 12q22 locus and one of therapeutic targets of human pancreatic cancer.
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Research Products
(6 results)
