中文摘要
口腔鳞癌最为颌面部最主要的恶性肿瘤，影响身心健康，重者危及生命。因高危型HPV感染与口腔鳞癌发生存在因果关系，本项目旨在从HPV感染致癌角度出发探索其发病机制，研究可能的免疫治疗方法。课题组应用已建立的口腔黏膜上皮细胞从正常到HPV永生化，逐步恶变的体外多因素、多阶段、多步骤癌变模型，采用基因芯片和蛋白组学分析技术筛选癌变相关基因和蛋白，结合临床组织标本对口腔鳞癌的分子发病机制进行研究，目前发现的癌变相关靶点基因有Annexin A1、Annexin A2、GDF15和CK17、CK19等，部分已进入基因功能研究阶段；建立Hu-PBL-SCID小鼠模型和HPV16 E6和E7恶性转化人口腔粘膜上皮细胞的体内致瘤模型；合成HPVE6和E7融合蛋白疫苗，观察其免疫学性质及治疗效果，动物实验结果显示该融合蛋白疫苗对实验性HPV相关口腔鳞癌有治疗作用，其机制可能是HPV疫苗诱导和激活体内NK细胞和CTL细胞，杀伤肿瘤，为口腔鳞癌的免疫治疗提供实验依据。
英文摘要
Oral squamous cell carcinoma (OSCC) is the most common malignant tumor in the oral and maxillofacial region. The mechanism of carcinogenesis of OSCC is still unclear. Based on our previous study, an in vitro multi-step cell model was established from normal human oral epithelial cell to cancerous cell that was transfected HPV16 E6/E7 gene and induced by benzo(a)pyrene.Genechip and comparative proteomic analysis were used as an innovative method to investigate the gene and protein expressions between cancerous and normal tissues/cells.Several differentially expressed proteins, such as Annexin A1, Annexin A2, GDF15, CK17, and CK19 et al, were identified and validated in the in vitro cellular carcinogenesis model and in the cancerous and paracancerous tissues from OSCC patients.HPV16 E6/E7/Hsp70 fusion protien vaccine was synthesized and immune reconstitution Hu-PBL-SCID mice model was established.The animal therapeutic experiment in vivo showed that the vaccine could could lead to regression of preexisting tumors.Its possible mechanism was induction and activation of NK and CTL cells. This fusion protein vaccine provides the scientific basis for the clinical application in the treatment of HPV-associated OSCC.
结题摘要
口腔鳞癌最为颌面部最主要的恶性肿瘤，影响身心健康，重者危及生命。因高危型HPV感染与口腔鳞癌发生存在因果关系，本项目旨在从HPV感染致癌角度出发探索其发病机制，研究可能的免疫治疗方法。课题组应用已建立的口腔黏膜上皮细胞从正常到HPV永生化，逐步恶变的体外多因素、多阶段、多步骤癌变模型，采用基因芯片和蛋白组学分析技术筛选癌变相关基因和蛋白，结合临床组织标本对口腔鳞癌的分子发病机制进行研究，目前发现的癌变相关靶点基因有Annexin A1、Annexin A2、GDF15和CK17、CK19等，部分已进入基因功能研究阶段；建立Hu-PBL-SCID小鼠模型和HPV16 E6和E7恶性转化人口腔粘膜上皮细胞的体内致瘤模型；合成HPVE6和E7融合蛋白疫苗，观察其免疫学性质及治疗效果，动物实验结果显示该融合蛋白疫苗对实验性HPV相关口腔鳞癌有治疗作用，其机制可能是HPV疫苗诱导和激活体内NK细胞和CTL细胞，杀伤肿瘤，为口腔鳞癌的免疫治疗提供实验依据。