| Co-Investigator(Kenkyū-buntansha) |
YAMAUCHI akira Kagawa Medical University, Dept. Cell Regulation, Professor, 医学部, 客員教授 (00291427)
YOKOMISE hiroyasu Kagawa Medical University, 2nd Dept. Surgery, Professor, 医学部, 教授 (80231728)
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| Budget Amount *help |
¥12,500,000 (Direct Cost: ¥12,500,000)
Fiscal Year 2002: ¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2001: ¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2000: ¥5,900,000 (Direct Cost: ¥5,900,000)
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| Research Abstract |
The integrin complexes located in cell membranes have a role in cell motility and tumor metastasis. During tumor progression, the downregulation of integrin complex-associated genes, such as MRP-1/CD9, KAI1/CD82, and integrin α3, occurs. These downregulations induce dysfunction of the integrin complexes, resulting in cancer cells with high metastatic potential. In order to suppress tumor metastasis, therefore, we have been studying gene therapies using the integrin complex-associated genes. We have studied various gene transfer methods, including adenovirus vectors, adeno-associated virus (AAV) vectors, and transferin-DNA complexes. We found that the adenovirus vector with CAG promoter and Kozak's sequence, Ad5-CD9 and Ad5-CD82, is the most potent vector for gene transfer. However, we have not succeed in producing AAV vectors. This might be because the sequences of both MRP-1/CD9 and KAI1/CD82 are too short to produce AAV vectors. In addition, transferin-DNA complexes have proven not t
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o be useful for clinical gene therapies, because of their low efficiency in gene transfer. From our results, both transfections of Ad5-CD9 into CD9-deficient cancer cell lines, and transfections of Ad5-CD82 into CD82-deficient cancer cell lines have shown effective gene expressions and expression of functional proteins in infected epithelial cancer cells. Experimental studies by transwell assay have demonstrated that transfections of MRP-1/CD9 or KAI1/CD82 can suppress motility of cell lines. In addition, studies of a spontaneous metastatic model using nude mice transplanted by cancer tissues revealed that injections of Ad5-CD9 or Ad5-CD82 suppressed lung metastasis, but not tumor growth. However, these adenovirus vectors are not considered appropriate for transfections into cell lines with high growth rates and hematological cell lines.
Therefore, we are going to perform further studies on cancer gene therapies using replicative adenoviral vectors specific for cancer cells, and cDNA microarray to elucidate their biological functions. Less
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