CAB39介导上皮间质转化在膀胱癌侵袭转移中的作用及机制研究

侵袭转移是恶性肿瘤的主要生物学特征。上皮-间质转化（EMT）在肿瘤侵袭转移中起重要作用，其分子机制不明。申请人前期研究发现CAB39基因在侵袭转移性膀胱癌组织中显著高表达，其表达量与膀胱癌细胞的侵袭转移潜能和癌组织中EMT相关蛋白Vimentin表达正相关和E-cadherin表达负相关；据此提出假设:CAB39通过调控EMT促进膀胱癌侵袭转移。本课题拟在组织标本中观察CAB39和EMT相关蛋白的相互作用，并分析它们与临床病理特征的相关性；通过基因稳定转染和干扰等技术在细胞和裸鼠模型中探讨CAB39表达改变对膀胱癌细胞生长和EMT的影响；进一步结合外源性TGF-β刺激实验和利用JNK抑制剂处理，观察其对EMT和JNK信号通路的影响，从而阐明CAB39通过JNK信号通路调控EMT发生，以促进膀胱癌侵袭转移的分子机制,为探寻膀胱癌基因治疗靶点和药物开发提供理论基础和实验依据。

Epithelial-mesenchymal transition (EMT) plays a significant role in the invasion and metastasis of cancer cells, the molecular mechanism of which remains to be elucidated. We previously found that CAB39 gene was highly expressed in invasive and metastatic bladder cancer. Expression level of CAB39 was closely related to invasive and metastatic potential of bladder cancer cells, while positively and negatively related to the two major EMT markers, Vimentin and E-cadherin, respectively. Therefore, we hypothesized that, CAB39 promotes invasion and metastasis of bladder cancer through regulation of EMT. In this project, we will establish a possible regulatory role of CAB39 in EMT-related proteins, and analyze their co-relations with clinical and pathological features of bladder cancer. Using gene manipulation measurements including stable transfection and knockdown techniques, we will study the effect of altering CAB39 expression on bladder cancer cell growth and EMT in cell and nude mice models, and on EMT and JNK signaling pathways by TGF-β stimulation and JNK inhibitors, respectively. In the aim of revealing the underlying molecular mechanism of CAB39 regulating EMT through JNK signaling pathway, this project will provide experimental data and theoretical basis for future development of gene targeted therapy and medicine for bladder cancer treatment.