| Project/Area Number |
15590357
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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 |
Experimental pathology
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| Research Institution | Sasaki institute |
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Principal Investigator |
OIKAWA Tsuneyuki Sasaki Institute, Department of Cell Genetics, Head, 細胞遺伝部, 部長 (80150241)
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| Co-Investigator(Kenkyū-buntansha) |
SUZUKI Mitsuhiro Sasaki Institute, Department of Cell Genetics, Research Associate (00321662)
櫻井 拓也 財団法人佐々木研究所, 細胞遺伝部, 研究員 (20353477)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2004: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2003: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Keywords | breast cancer / transcription factor / Ets / Fli-1 / malignancy / apoptosis / bcl-2 / MMP / Fli-1 / Etsがん遺伝子 / 膵臓癌 / 薬物耐性 / マイクロアレイ |
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| Research Abstract |
Positive correlation was found between the expression levels of several Ets family genes and invasion-related genes such as the uPA(urokinase-type plasminogen activator) and MMP(matrix metalloproteinase) genes in human malignant tumor cell lines including 11 mammary tumors and 4 pancreatic tumors. There are many reports concerning about tight correlation between the expression level of Ets-1 and tumor malignancy. However, the role of Fli-1 in solid tumors has not been elucidated well. Therefore, we introduced an expression vector of Fli-1 into MCF-7 human low-malignant mammary tumor cells to get several clones expressing high levels of Fli-1 protein. There were not so significant differences between Fli-1-transfectants and mock-transfectants in growth under culture conditions with 10% and 1% fetal bovine serum. However, Fli-1-transfectants were more resistant to apoptotic cell death induced by serum depletion than mock-transfectants. Expression of Fli-1 and bcl-2 was induced by serum d
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epletion and the expression levels were higher in Fli-1-transfectants than mock-transfectants. The induction was suppressed by adding a JNK (Jun terminal kinase) inhibitor, suggesting that JNK is in volved in induction of Fli-1 and bcl-2 expression by serum depletion. Fli-1-transfectants also showed the higher rates of inhibition of apoptosis by UV-irradiation. Since the bcl-2 gene has Ets-binding sites on its promoter region, it is likely that enhanced Fli-1 expression in solid tumors plays a critical role in inhibition of apoptosis. By using siRNA, we then examined the functional roles of other Ets family genes whose expression is often enhanced in human mammary tumors. Highly malignant MDA-MB-231 human mammary tumor cells were transfected with siRNA against the Ets-1,Ets-2,ER81 or E1A-F gene. Expression of the MMP-1,MMP-3 and MMP-9 genes was down-regulated accompanied by suppression of Ets-1 expression with siRNA against Ets-1 in the cells. Expression of the MMP-1,MMP-3 and MMP-7 genes was down-regulated with siRNA against Ets-2. No changes were observed in expression of the MMP genes with siRNA agaist ER81,although introduction of the siRNA resulted in suppression of expression of the bad gene. These results suggest that the Ets family genes highly expressed in the same tumors participate in malignancy by affecting expression of individual or common target genes. Less
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