eIF4E在miR-206的调控下通过影响ROS反应参与肝细胞癌发生发展的机制研究

Hepatocellular carcinoma (HCC) is a malignant tumor with high incidence and mortality. However, the precise mechanism of its development is still elusive. We have found that eukaryotic initiation factor 4E (eIF4E) was over-expressed in HCC and its expression was related to the prognosis of HCC patients, which showed eIF4E was an independent risk factor of HCC. At the protein level, the expression of eIF4E in HCC cell lines was higher than that in normal liver cells L02, while there was an opposite result at the RNA level. Moreover, miR-206 could specifically bind to the 3’ untranslated region of eIF4E and there was also an evidence that eIF4E was a direct target of miR-206. Recent researches reported that eIF4E was involved in the development of lung cancer through influencing the response of cancer cells to reactive oxygen species (ROS) by promoting the translation of oxidative stress response genes like Fth1. Therefore, we surmise that eIF4E participates in the development of HCC by influencing the response of cancer cells to ROS under the regulation of miR-206. Our research will study the regulation effect of miR-206 on eIF4E and the effect of eIF4E in the response of HCC cells to ROS by setting up models of eIF4E and miR-206 in vitro and vivo, and provide new clues and strategies to the research of HCC development mechanism and clinical treatment.

肝细胞癌（HCC，简称肝癌）是一种死亡率高的恶性肿瘤，然而其发生发展机制仍不清楚。本课题组前期发现在肝癌组织中高表达的真核起始因子4E（eIF4E）与肝癌患者的预后相关。在蛋白水平，eIF4E在肝癌细胞中的表达水平高于正常肝细胞L02，而在RNA水平，eIF4E在肝癌细胞系中的表达水平低于L02。miR-206可与eIF4E 3’非翻译区特异性结合，有研究证实eIF4E是miR-206的直接靶点。最新研究表明eIF4E通过促进氧化应激反应基因Fth1的翻译，影响肿瘤细胞对活性氧（ROS）的应激，参与肺癌发生发展。因此，我们推测：eIF4E在miR-206调控下通过影响ROS反应参与肝癌的发生发展。本课题拟构建eIF4E和miR-206高、低表达体内外模型，研究miR-206对eIF4E的调控作用以及eIF4E在肝癌细胞ROS反应中的作用，为探究肝癌的分子病理机制和临床治疗提供新的线索和策略

肝细胞癌（HCC，简称肝癌）是一种死亡率高的恶性肿瘤。本课题组前期发现在肝癌组织中高表达的真核起始因子4E（eIF4E）与肝癌患者的预后相关，然而其参与肝癌发生发展的机制尚不明确。我们利用基因过表达及干扰技术，证实miR-206以eIF4E为靶点，负向调控eIF4E的表达；体外功能学实验表明eIF4E促进肝癌细胞的增殖、迁移和侵袭，抑制肝癌细胞的凋亡；体内实验表明eIF4E促进瘤体生长；机制研究表明eIF4E调控Fth1的表达，影响凋亡相关蛋白、细胞周期相关蛋白以及MAPK通路相关蛋白的表达。另外，本项目还发现eIF4E促进肝癌细胞对索拉菲尼耐受。本研究将eIF4E和肝癌的病理生理发生过程联系在一起，为研究eIF4E在肝细胞癌中的功能提供新的线索。