Association of signal transduction for TLR-4 with oral cancer

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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 … More 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