Akirin2通过NF-κB信号通路促进膀胱癌发生发展的机制研究

Bladder cancer is one of the most common malignant tumors worldwide. The identification of new biomarkers for bladder cancer and a better understanding of the molecular mechanisms underlying bladder carcinogenesis will improve the diagnosis and treatment of BC. Our previous study showed that the expression of Akirin2 was up-regulated in human BC tissues. Silencing of Akirin2 inhibited cancer cell proliferation and metastasis in vitro. Mechanistically, Akirin2 interacted with NF-κB subunit p65. We speculate that Akirin2 influences bladder cancer tumorigenesis via regulating the activation of NF-κB signaling. Based on our previous study, we first aim to analysis the correlation between the expression of Akirin2 and bladder cancer grade. Second, we use co-immunoprecipitation assay and confocal fluorescence to implore the co-localization and the interaction between Akirin2 and p65. Next we plan to predict the important amino acid site mediated the interaction between Akirin2 and p65, and then mutate the critical amino acid site to illuminate the mechanism of Akirin2 in bladder cancer tumorigenesis. Together, the present study may provide insights for understanding the mechanism of bladder cancer tumorigenesis. Morever, it will provide Akirin2 as a candidate prognostic biomarker and target for new therapies in human bladder cancer.

膀胱癌是泌尿系统最常见的恶性肿瘤，预后差、复发率高。膀胱癌的治疗除了常规的手术，放化疗外，并无特异的治疗靶点。因此，探索膀胱癌发生发展的分子机制，寻找特异的治疗靶点显得尤为迫切。我们的前期研究发现：Akirin2在膀胱癌组织中表达上调，敲低Akirin2的表达显著抑制膀胱癌细胞增殖以及转移，并且Akirin2与NF-κB重要亚基p65相互作用。我们推测：Akirin2通过NF-κB信号通路影响膀胱癌的发生发展。我们拟开展如下研究：第一，利用免疫组化技术，分析Akirin2的表达与膀胱癌临床分期以及病理分级的关系。第二，利用蛋白质免疫共沉淀技术和荧光共聚焦技术，研究Akirin2与p65的相互作用及共定位。第三，利用生物信息学预测介导相互作用的关键氨基酸位点，将关键氨基酸位点突变，深入阐述相互作用对于功能发挥的必要性。本研究可为膀胱癌的治疗以及筛选药物靶点提供理论基础和新思路，具有指导意义。

膀胱癌是泌尿系统最常见的恶性肿瘤，也是十大全身性肿瘤之一。近年来，膀胱癌发病率和死亡率均呈上升趋势，而且膀胱癌的预后不佳，是导致膀胱癌患者死亡的主要原因。因此,研究膀胱癌发生、发展的相关机制具有重要的意义。深入理解膀胱癌发生发展的分子机制将有助于发现新的治疗靶点以及新的治疗策略。肿瘤发生与机体固有免疫系统异常密切相关。我们通过大规模的RNAi筛选发现，Akirin2和TBK1两个在固有免疫中发挥重要作用的蛋白在膀胱癌的发生发展中也发挥了重要的作用。Akirin2通过与p65相互作用显著抑制NF-kB通路报告基因的激活以及NF-kB下游基因的表达。TBK1可能以Akt依赖的方式赋予膀胱癌细胞的恶性表型，为开发膀胱癌新型治疗靶标提供了新的思路。