AIM2靶向FN1抑制肝癌细胞转移的机制研究

浸润转移是导致肝细胞癌预后差的主要因素，但其分子机制尚未明了。我们前期观察到AIM2在肝癌细胞及组织中低表达，并与血管侵犯、淋巴结转移及预后差相关；基因芯片及细胞实验结果表明沉默AIM2显著上调FN1表达，并促进肝癌细胞迁移；此外，AIM2表达受HBx调控。因此，我们提出AIM2靶向FN1，抑制肝癌细胞转移的假说。本项目拟采用一系列分子细胞生物学和免疫学实验，利用多种细胞株和动物模型，在细胞功能及蛋白表达调控上，明确AIM2和FN1在肝癌中的表达及临床意义，揭示HBx调控AIM2的作用机制，探讨AIM2对FN1的调控作用，阐述HBx/AIM2/FN1通路在肝癌细胞转移中的作用及其分子机制，从而获得AIM2参与肝癌恶性进程的可靠证据，为寻找肝癌治疗新靶点和诠释肝癌发生发展的分子机制提供科学依据。

Tumor invasion and metastasis are responsible for the poor prognosis of hepatocellular carcinoma (HCC). However, the underlying mechanism remains elusive. Our preliminary data showed that the expression of AIM2 in HCC was decreased and significantly correlated with vascular invasion, lymph node metastasis and poor prognosis. Downregulation of AIM2 markedly induced the expression of FN1, and promoted cell migration and invasion. Furthermore, AIM2 expression was modulated by HBx. Collectively, we assume that AIM2 inhibits cell migration and invasion of HCC by targeting FN1. In this study, we aim to determine the expression of AIM2 and FN1 and the relevant clinical significance in HCC, to disclose the effect of HBx on AIM2, to unveil the mechanism of AIM2-mediated regulation of FN1 expression, and to reveal the role of HBx/AIM2/FN1 signaling pathway in cell migration and invasion in HCC, using a series of biological and immunological experiments in cell and animal models. Our study is likely to provide not only solid evidence that AIM2 is involved in HCC progression, but also a promising therapeutic target in HCC.