AGO1对α干扰素抑制肝细胞癌转移复发的影响及机制研究

作为非编码小RNA (miRNA) 的主要结合蛋白，AGO1通过与miRNA结合形成沉默复合体（RISC）参与调控RNA基因沉默。这一调控作用在肿瘤进展中发挥重要功能。前期工作中，我们发现α干扰素的抗肝癌作用可能依赖于HIF-1α的低表达。有研究表明，AGO1通过对miRNA的调控参与HIF的功能实现。同时，我们发现AGO1与特定的miRNA表达和α干扰素治疗敏感性相关。因此，AGO1及相关miRNA可能在α干扰素抗肝癌治疗中起关键作用。本项目拟利用我所最先建立的不同转移潜能人肝癌细胞株、裸鼠模型及肝癌临床组织标本，通过高通量基因筛查、组织芯片和基因转染等技术，结合生物信息学方法，探讨AGO1相关的特定miRNA调控肝癌细胞对α干扰素敏感性的机制，构建疗效预测分子模型，对提高α干扰素疗效和改善肝癌预后有重要意义。

As noncoding small RNA combining protein, AGO1 contains a PIWI domain which owns potential RNaseH activity and is the active center of RNA-induced silencing complex (RISC). AGO1 forms RISC with MicroRNA (miRNA), and the latter is involved in RNA silencing. This regulatory effect significantly influences tumor metastasis. Our previous studies indicated that 1) high dose interferon α (IFN-α) therapy has a HIF-depended suppressive effect on hepatocellular carcinoma (HCC) angiogenesis, metastasis and recurrence, 2) the expression of AGO1 affects HIF functioning and is associated with HCC metastasis, recurrence and prognosis, and 3) miRNA profile is associated with HCC sensitivity to IFN-α. The present project bases on HCC cell lines and in situ nude mice HCC metastatic models established firstly by our institute and clinical HCC specimens. We will use gene microarray, tissue microarray, and stable transfection by Lentivirus. Medical informatics calculations will be performed. The aims are to clarify the functions of AGO1 in certain related miRNA, how these miRNA regulate HIF-1α function, and finally the influence on IFN-α sensitivity. We will further investigate the underlying mechanism, and search for proper molecular models in order to elevate the therapeutic value of IFN-α and improve HCC prognosis.