Basic investigation on moledules which regulate the sensitivity of oral squamous cell carcinoma (cells) to chemo-radio-immunotherapy

口腔鳞状细胞癌（细胞）放化疗敏感性调节分子的基础研究

基本信息

批准号：
14370676
负责人：
OSAKI Tokio
金额：
$ 6.66万
依托单位：
Kochi Medical School
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370676/
关键词：
oral cancer invasion reactive oxygen species Mn-SOD tight junction occludin claudin β-catenin 活性酵素

项目摘要

A) We treated oral carcinoma patients by chemo (5-FU and peplomycin)-radio (γ-rays)-immunotherapy (OK-432 and LAK cells) and examined genes and proteins which were associated with the therapeutic effects and lymph node metastasis.B) Using squamous cell carcinoma (SCC) cell lines established from lymph-metastasized oral SCC, we investigated apoptosis-regulating genes and molecules.The results are as follows.A-1. The microarray analysis suggested that the expression of COMT (Catechol-O-methyltransferase) was negatively correlated with lymph node metastasis while C-CAM1 (Carcinoembryonic antigen-related cell adhesion molecule1) was positively correlated with lymph node metastasis and that the expression of MFG-E8 (Milk fat globular-EGF-factor 8) was positively correlated with the effect of chemo-radio immunotherapy.B-1. The in vitro sensitivity of SCC cell lines to the anticancer agents was inversely correlated with the reactive oxygen species (ROS)-scavenging activity, especially Mn-supe … More roxide dismutase (SOD) activity of the cancer cells. The intracellular ROS increased the phosphorylation of the Bcl-2 family proteins and the increased phosphorylation of Bax and Bcl-2 induced a decrease and an increase of their ubiquitination, respectively. Accordingly, these effectsof ROS were inhibited by transfection of Mn-SOD antisense or SCC treatment with antioxidants.B-2. In SCC cells possessing a highly invasion activity, E-cadherin, one of tight junction structural components, was weakly expressed compared with that in non-ivasive SCC cells, while claudin 1, one of adherens junction components, was strongly expressed in highly invasive SCC cells. The level of E-cadherin expression was inversely correlated with the SCC cell sensitivity to the anticancer agents.B-3. The expression level of hypoxia inducile factor-1a (HIF-1a) was increased by cultivation of SCC cells in hypoxic condition (1% oxygen) for longer than 12 h or by their treatment with the anticancer agents. The expression level of HIF-1a was negatively correlated with the susceptibility of SCC cells to the anticancer agents. Knockdown of HIF-1a by siRNA induced a high susceptibility to the anticancer agents.ConclusionThese results indicate that the expression levels of the MFG-E8 gene, E-cadherin, caludin 1 and HIF-1a as well as the ROS scavenging activity are indicative of the susceptibility of SCCs to chemo-radio-immunotherapy and the suggest that the down-regulation of Mn-SOD and HIF-1a is an useful strategy for oral SCC treatment. In addition, regional lymph node metastasis couldbe predicted by the expression pattern of COMT or C-CAM1 gene. Less

a）我们通过化学疗法（5-FU和胃霉素） - 亚adio（γ射线） - 免疫疗法（OK-432和LAK细胞）治疗了口腔癌患者，并使用Squamous Carcin coc cc cc cc cc cc cc cc cc cc cc cc cc cc s cc s cc s cc s cc s cc s cc s cc cy s s cc s cc cc s s cc cc cocc.-ok-432和lak细胞）治疗了基因和蛋白质的基因和蛋白质研究了凋亡调节基因和分子。结果如下。A-1。 The microarray analysis suggested that the expression of COMT (Catechol-O-methyltransferase) was negatively correlated with lymph node metastasis while C-CAM1 (Carcinoembryonic antigen-related cell adhesive molecule1) was positively correlated with lymph node metastasis and that the expression of MFG-E8 (Milk fat global-EGF-factor 8) was positively与化学拉迪奥免疫疗法的作用相关。B-1。 SCC细胞系对抗癌药的体外敏感性与反应性氧（ROS） - 扫描活性，尤其是Mn-Supe…更多的癌细胞活性相关。细胞内ROS增加了Bcl-2家族蛋白的磷酸化，而Bax和Bcl-2的磷酸化增加分别诱导了其泛素化的降低和增加。彼此之间，通过用抗氧化剂转染MN-SOD反义或SCC处理来抑制ROS的这些作用。B-2。在具有高度侵袭活性的SCC细胞中，与非视和性SCC细胞相比，E-钙粘蛋白是紧密连接结构成分之一，而Claudin 1（一种粘附的连接组件之一）在高度侵入性的SCC细胞中强烈表达。 E-钙粘蛋白表达的水平与SCC细胞对抗癌剂的敏感性成反比。B-3。通过在缺氧条件下的SCC细胞（1％氧）培养超过12小时或通过用抗癌剂治疗的SCC细胞，增加了缺氧诱导的因子1a（HIF-1A）的表达水平。 HIF-1A的表达水平与SCC细胞对抗癌剂的敏感性负相关。 Knockdown of HIF-1a by siRNA induced a high susceptibility to the anticancer agents.ConclusionThese results indicate that the expression levels of the MFG-E8 gene, E-cadherin, caludin 1 and HIF-1a as well as the ROS scavenging activity are indicative of the susceptibility of SCCs to chemo-radio-immunotherapy and the suggest that the down-regulation of Mn-SOD and HIF-1a is an口服SCC治疗的有用策略。另外，可以通过COMT或C-CAM1基因的表达模式预测区域淋巴结转移。较少的