FOXO3a通过FAK/Src黏附通路应对氧化应激促进肝癌侵袭转移的机制研究

肝癌转移是其预后不良的重要原因，氧化应激是影响循环肿瘤细胞转移的关键。FOXO3a作为应激调控的重要分子，在肝癌转移中的机制尚不明确。前期发现高表达FOXO3a显著促进肿瘤转移；转录组测序提示FOXO3a与细胞黏附通路密切相关，并影响细胞外基质蛋白THBS1表达。而THBS1可结合整合素受体并激活FAK/Src通路。据此，我们推测：氧化应激诱导循环肿瘤细胞中FOXO3a活化，促进THBS1表达并分泌到细胞表面形成保护膜，活化整合素受体并激活FAK/Src通路，抵抗失巢凋亡并促进黏附运动，有助于肝癌转移。本研究拟通过体内外实验明确FOXO3a激活FAK/Src黏附通路促进肝癌转移的分子机制，借助免疫共沉淀和双荧光素酶报告实验等阐明THBS1受到FOXO3a调控，介导整合素受体活化和FAK/Src黏附通路的激活。本研究是FOXO3a参与肿瘤进展机制的重要补充，为防治肝癌转移复发提供新思路。

Metastasis and recurrence seriously affect the long-term prognosis of patients with hepatocellular carcinoma (HCC). Oxidative stress is a key factor to inhibit circulating tumor cells metastasis. The mechanism of FOXO3a as an important factor of stress regulation in the process of HCC metastasis remains unclear. Our previous study showed that high expression of FOXO3a significantly promoted tumor metastasis in mouse model of tail vein injection; RNA-sequencing analysis revealed that FOXO3a was closely related to cell adhesion pathway and significantly affected the expression of extracellular matrix protein THBS1. Considering that THBS1 binds to integrin receptors and activates FAK/Src pathway, we hypothesize that FOXO3a is activated by oxidative stress in circulating tumor cells, and then promotes THBS1 expression and secretion to the cell surface to form protective membranes, activating integrin receptors and FAK/Src pathway to promote anoikis resistance and adhesion motility contributing to tumor metastasis. Here, we intend to clarify the mechanism of FOXO3a activating FAK/Src adhesion pathway to promote HCC metastasis through in vivo and in vitro experiments, and elucidate the mediating role of THBS1 in activating integrin receptor and FAK/Src adhesion pathway by immunoprecipitation and dual-luciferase reporter assay. This study will help to further understand the function of FOXO3a in HCC metastasis, and provide new strategy for HCC treatment.