新候选抑癌基因FOXN1核移位抑制自噬在胃肠肿瘤进展中的作用机制研究

我们前期预实验结果发现Forkhead box基因家族成员FOXN1在50%以上的胃肠肿瘤组织中表达显著下降或沉默，并与患者的预后密切相关；FOXN1转染后能抑制肿瘤细胞增殖，过氧化氢处理能通过PI3K通路促进FOXN1核移位并抑制肿瘤细胞自噬，生物信息学预测FOXN1能与AKT1和SIRT1等自噬相关的重要蛋白相互结合。本项目将研究FOXN1在胃肠肿瘤组织中的表达及其临床意义，验证miR-518b、miR-192-5p或miR-1306对FOXN1的表达调控；同时通过上调或下调FOXN1在肿瘤细胞中的表达，体内外实验阐明其在胃肠肿瘤进展中所起的生物学作用及分子机制，尤其对FOXN1是否通过核移位调控细胞在不同应激状态下的自噬及与肿瘤细胞归属的关系进行深入研究，明确FOXN1在自噬中的具体作用及作用靶点，希望从分子水平为基于FOXN1的胃肠肿瘤诊断和治疗提供科学依据。

Our preliminary experimental results suggested that FOXN1, the member of the Forkhead gene family, was significantly down-regulated or silenced in more than 50% of gastrointestinal cancer cases and its protein expression level was closely related to the prognosis of the patients. Restoring FOXN1 expression in gastric cancer cell line AGS and colon cancer cell line HT-29 can dramatically inhibited cancer cell proliferation. Hydrogen peroxide treatment could affect FOXN1 nuclear translocation through PI3K pathway to regulate cell autophagy. Bioinformatics predicted that FOXN1 can combine with autophagy related important proteins such as AKT1 and SIRT1. This project will study FOXN1 expression and its clinical significance in gastrointestinal cancer, verify the FOXN1 expression control mechanism of miR-518b, miR-192-5p and miR-1306. Meanwhile, we will explore by in vitro and in vivo experiments that whether FOXN1 gene plays an important biological function in gastrointestinal cancer progression and the molecular mechanisms, especially whether FOXN1 affect autophagy through nuclear translocation under different cell stress states. We will also clarify the specific role and the target of FOXN1 in controlling autophagy. This study will provide scientific basis for gastrointestinal cancer diagnosis and theatment based on FOXN1.