| Project/Area Number |
17591943
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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 |
Functional basic dentistry
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| Research Institution | Kagoshima University |
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Principal Investigator |
OHNISHI Tomokazu Kagoshima University, Graduate School of Medical and Dental Sciences, Associate Professor, 大学院医歯学総合研究科, 助教授 (30244247)
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| Co-Investigator(Kenkyū-buntansha) |
MATSUGUCHI Tetsuya Kagoshima University, Graduate School of Medical and Dental Sciences, Professor, 大学院医歯学総合研究科, 教授 (10303629)
KAKIMOTO Kyoko Kagoshima University, Graduate School of Medical and Dental Sciences, Research Associate, 大学院医歯学総合研究科, 助手 (40274849)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2006: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2005: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | oral cancer / TLR-4 / HGF / c-met / JNK / TLR / MyD88 / 炎症 |
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| Research Abstract |
We examined if the generation of oral cancer was associated with the oral bacteria induced inflammation, that was mainly mediated though TLR-4. Among TLR-4 signal transducing molecules, we focused on MyD88 and MAP kinase phosphatase-macrophage (MKP-M), which was phosphatase for JNK1/2. We prepared myd88 genome altered mice and mkpm genome altered mice, in which MKP-M protein was inactivated. These mice were treated with 4-nitroquinoline 1-oxide (4-NQO) as a carcinogen material to induce oral cancer. Histological analysis showed carcinogenesis in tongues from control mice treated with 4-NQO. However a decrease in carcinogenesis was observed in myd88 genome altered mice in which the response against bacteria was reduced compared with control mice. Furthermore, a greater carcinogenesis was observed in MKP-M inactivated mice. Next we isolated total RNA from these tongues, and then we performed reverse transcription PCR and real time PCR to measure the expression of c-met which was found as
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a protoncogene and known to be a receptor of hepatocyte growth factor (HGF). The expression of c-met increased in tongues from control mice treated with 4-NQO, whereas its expression in tongue from myd88 genome altered mice treated with 4-NQO was the same level as that from non-treated control mice. While on the other hand, the expression of c-met increased in tongues from MKP-M inactivated mice treated with 4-NQO compared with 4-NQO treated control mice. These results of PCR consistent with histological analysis of 4-NQO treated tongues.
Next, we established fibroblasts by outgrowth form gingiva, and stimulated cultured gingival fibroblasts with IL-1 and/or LPS. And then we performed reverse transcription PCR and real time PCR to measure the expression of c-met and HGF. Consequently, these stimulations did not increase HGF and c-met expressions in myd88(-/-) fibroblasts. On the other hand, the expression of HGF increase in gingival fibroblasts from MKP-m genome altered mice by stimulations with IL-1 and/or LPS, these results were consists with our previous reports which described changes of expression of HGF in normal gingival fibroblasts. These observations suggested that IL-1 and TLR-4 signal induced HGF expression mediated through MyD88 pathway. Enhancement of HGF expression by stimulation with bacteria and IL-1 associated with growth of oral cancer cells.
In summary, activation of TLR-4 signal transduction pathway (such as MyD88 and JNK1/2 mediated pathway) by infections of oral bacteria plays an important role in oral carcinogenesis mediated through increase the expression of c-met and HGF. Less
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