Annexin A5介导的PI3K/Akt/NF-κB通路在胶质瘤侵袭中的作用及机制

A number of studies have shown that Annexin A5 is one of biological markers of malignant tumors. Annexin A5 expresses abnormally in many kinds of maligant tumors such as prostate cancer,liver cancer,and lung cancer and plays different biological effects, however the concrete mechanism is still unknown. The results of our preliminary tests showed that Annexin A5 can enhance invasion ability of glioma cells and upregulate Snail mRNA and protein through PI3K/Akt signal pathway. As one of downstream molecules of Akt, NF-κB can not only stablize the protein of Snail against degradation,but also increase Snail expresson at transcription level.We speculated that NF-κB is involved in biological effects of Annexin A5 in glioma cells by reviewing recent literature. In other words, Annexin A5 evoke invasion of glioma cells through the activation of PI3K/Akt/ NF-κB signaling pathway. To verify our hypothesis, the concrete mechanism will be further analyzed by technologies of recombinant virus, western blot ,etc in vitro and vivo on the basis of our previous tests.The implementation of the project will provide strong theoretical basis and a new target for molecular pathological and targeted therapy of glioma.

多项研究表明，Annexin A5是一种恶性肿瘤生物学标记，Annexin A5在前列腺癌、肝癌、肺癌等多种恶性肿瘤中异常表达，发挥不同生物学作用，其具体机制不详。课题组前期试验国内外首次发现：Annexin A5可通过PI3K/Akt信号传导通路增强胶质瘤细胞的侵袭能力并引起Snail mRNA及蛋白的上调。Akt下游众多分子信号中，NF-κB在侵袭相关因子Snail的调控方面尤其是在转录水平的调控中发挥重要作用，结合前期试验结果及近期文献，我们推测NF-κB参与了Annexin A5对胶质瘤细胞生物行为学的影响，即Annexin A5通过激活PI3K/Akt/NF-κB信号通路促进胶质瘤侵袭。本研究拟在组织、细胞、动物实验多个层面通过重组慢病毒技术、Western blot技术等进一步分析Annexin A5促进胶质瘤侵袭的具体机制，为胶质瘤的诊断及靶向性治疗提供新的靶点及依据。

多项研究表明，Annexin A5是一种恶性肿瘤生物学标记，Annexin A5在前列腺癌、肝癌、肺癌等多种恶性肿瘤中异常表达，发挥不同生物学作用，其具体机制不详。课题组前期试验国内外首次发现：Annexin A5可通过PI3K/Akt信号传导通路增强胶质瘤细胞的侵袭能力并引起Snail mRNA及蛋白的上调。Akt下游众多分子信号中，NF-κB在侵袭相关因子Snail的调控方面尤其是在转录水平的调控中发挥重要作用，结合前期试验结果及近期文献，我们推测NF-κB参与了Annexin A5对胶质瘤细胞生物行为学的影响，即Annexin A5通过激活PI3K/Akt/NF-κB信号通路促进胶质瘤侵袭。本研究在临床病理组织发现了Annexin A5在胶质瘤中的表达与级别相关，并且不同级别肿瘤中p-PI3K、p-AKt、p65的表达与Annexin A5的表达相关性明显；体外细胞实验发现Annexin A5通过PI3K/AKt增强Snail启动子转录活性，并促进p65在Snail启动子富集；动物实验显示Annexin A5明显促进裸鼠颅内肿瘤的生长。本项目从组织、细胞、动物实验三个层面出发阐明了Annexin A5促胶质瘤侵袭的机制，为胶质瘤的诊断及靶向性治疗提供新的靶点及依据。