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A new anti-cancer strategy by control ling cross talk of oral carcinoma cells with extra cellular matrix molecules

控制口腔癌细胞与细胞外基质分子串扰的新抗癌策略

基本信息

批准号：
13557157
负责人：
SAKU Takashi
金额：
$ 9.02万
依托单位：
Niigata University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

项目摘要

In order to study a possibility of anti-cancer effect of inhibition of oral carcinoma cells' cross talk with extracellular matrix molecules, we examined various interactions between oral carcinoma cells and stromal fibroblasts by using cell lines, such as ACC3 or ACCM cells which were derived from human adenoid cystic carcinomas, and ZK-1 or MK-1 cells, which were derived from human squamous cell carcinomas.First of all, we examined the effect of suramin, a polysulfonated naphthylurea, on biosyntheses of extracellular matrix (ECM) molecules and their receptor integrins as well as their interaction in ACC3 cells. Suramin enhanced secretion of ECM molecules by ACC3 cells into the culture medium, and it inhibited ACC3 cells to attach in a short-term culture, that was enhanced in the presence of RGD peptides. The molecular mechanism of this phenomenon was proved by our experiments using metabolic labeling, immunoprecipitation, and immunoblotting, RT-PCR, and DNA microarrays. Suramin inhibi … More ted the biosynthesis of focal adhesion kinase (FAK) and its assembly into the cell membrane via integrins. At the same time tyrosine phosphorylation of FAK and other molecules were inhibited by suramin, although the gene expression levels for integrins and FAK were not suppressed. The results indicated that enhanced secretion of ECM molecules might result from inability of ACC3 cells to trap them on their cell surface by way of integrins, because integrins failed to be sorted and to be assembled into the cell membrane due to the absence of FAKAt the same time, the important role of extracellular matrix molecules, especially perlecan, in cellular proliferation was approved in various oral tumor or embryonal cells as well as stromal cells. Perlecan was also shown to be degraded constantly in physical conditions in oral tumor cells, which may indicate that it is metabolized by them for their growth.Based on the data obtained in this study, it is highly suggested that oral carcinoma cells require crosstalk with extracellular matrix for their survival and that their proliferation could be suppressed by the inhibition of their recognition of extracellular, matrix. Less

为了研究抑制口腔癌细胞与细胞外基质分子串扰的可能性，我们利用人腺样囊性癌来源的ACC3或ACCM细胞和人鳞状细胞癌来源的ZK-1或MK-1细胞系，研究了口腔癌细胞与间质成纤维细胞之间的各种相互作用。首先，我们研究了聚磺化萘脲苏拉明对ACC3细胞细胞外基质(ECM)分子及其受体整合素的生物合成及其相互作用的影响。苏拉明促进ACC3细胞向培养液中分泌ECM分子，并在短期培养中抑制ACC3细胞的贴壁，这种抑制作用在RGD多肽存在下被增强。通过代谢标记、免疫沉淀、免疫印迹、RT-PCR和DNA微阵列等实验，证实了这种现象的分子机制。苏拉明抑制…进一步研究了粘着斑激酶(FAK)的生物合成及其通过整合素组装到细胞膜上的过程。同时，尽管整合素和FAK的基因表达水平不受抑制，但苏拉明对FAK和其他分子的酪氨酸磷酸化有抑制作用。结果提示，细胞外基质分子的分泌增加可能是由于细胞不能通过整合素将其捕获到细胞表面，因为整合素的缺乏导致整合素不能被分离和组装到细胞膜上。同时，各种口腔肿瘤或胚胎细胞以及基质细胞都证实了细胞外基质分子，尤其是细胞外基质分子在细胞增殖中的重要作用。在物理条件下，Perlecan在口腔肿瘤细胞中也被不断降解，这可能表明它被口腔肿瘤细胞代谢以促进其生长。根据本研究获得的数据，高度建议口腔癌细胞的生存需要与细胞外基质的串扰，并且可以通过抑制其对细胞外基质的识别来抑制其增殖。较少