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我们的研究项目“膀胱癌特异性肿瘤标志物的筛选鉴定和致癌机理的研究” 获得国家自然科学基金面上项目资助

时间 : 2011-01-15


摘要:特异的肿瘤标志物一直是膀胱癌研究的热点,利用与膀胱癌特异结合的抗体,分离、鉴定膀胱癌相关抗原,不仅能进一步认识膀胱癌形成的分子机制,而且为膀胱癌的诊断与治疗提供新的生物靶点。我们用杂交瘤技术筛选到一株抗人膀胱癌单克隆抗体mAbBC1mAbBC1 单抗对人膀胱癌组织和膀胱癌细胞系EJ T24 呈强阳性反应,而与正常人膀胱组织呈阴性反应,与正常人胚胎组织和其它正常组织也无交叉反应。在细胞水平和动物水平,mAbBC1 单抗能有效控制肿瘤细胞的增殖、迁移、粘附和侵袭,显著抑制裸鼠移植瘤的生长。本课题将在mAbBC1 单抗分离纯化抗原的基础上,鉴定该抗原的理化性质与生物学功能,确定该抗原的基因和氨基酸序列,探明其在肿瘤细胞中的主要信号通路,研究其在膀胱癌不同病理分期与肿瘤分级中的表达差异,最终阐明该抗原在膀胱癌中的致癌机理,建立膀胱癌早期预警和预后监测系统,为膀胱癌体外诊断及靶向治疗提供理论和实验依据。

Abstract: Bladder cancer is one of the most common malignancies, which is usually treated by surgical resection and intravesical chemo- and immunotherapy. Following treatment, about 70% of these tumors will recur. The major issue in bladder cancer is prediction of recurrence and progression by using biomarkers that could be potentially targeted in therapies. The α3β1 integrin (CD49c/CD29) serves as a high-affinity receptor for laminin, fibronectin and collagen. The aberrant glycosylated α3β1 integrin was abundantly expressed in bladder cancer primary and metastatic tissues, whereas its expression in normal bladder parenchyma was observed at very low levels. In the present study, we used an antibody-based approach and identified mAbBC1 as a novel anti-aberrant glycosylated α3β1 integrin antibody. This antibody showed restricted binding to aberrant glycosylated α3β1 integrin expressed in bladder cancer. The binding of mAbBC1 to bladder cancer cells but not to normal ureter and bladder epithelium and other non-bladder cell lines was confirmed. This antibody only stained bladder tumor tissues after screened 123 tumor tissues and 56 normal tissues by immunohistochemistry. The BC1 antigen, aberrant glycosylated α3β1 integrin, was correlated with pathological grades and Dukes stages. It can be recognized as specific markers of bladder cancer supporting screening, initial diagnosis, surveillance for recurrent lesions, detection of early progression, and prediction of the biological potential of a particular tumor with the ultimate aim to alter clinical patient management. mAbBC1 specifically decreased cell-substrate and increased cell-cell adhesion, moreover, it can promote NK cells-mediated destruction of tumor cells. mAbBC1 efficiently inhibited the proliferation and migration of bladder cancer cells and human tumor growth in xenografted tumor models in mice. Further studies had shown that mAbBC1 controlled cyclin D1 expression by reducing mitogen-activated protein kinase activity in tumor cells. These results provide a strong rationale for investigating antibody-based, aberrant glycosylated α3β1 integrin-targeted therapies in bladder cancer.

 


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