Forkhead box G1 (FOXG1) is a member of the Fox transcription factor family involved in regulation of many cancers. However, the role of FOXG1 in hepatocellular carcinogenesisis largely unclear. The present study aimed at examining the biological function and underlying mechanism of FOXG1 on hepatocellular carcinoma (HCC) tumor metastasis as well as its clinical significance. Levels of FOXG1 were determined by immunohistochemical and real-time PCR analysis in HCC cell lines and human HCC samples. The effect of FOXG1 on cancer cell invasion and metastasis was investigated in vitro and in vivo in either FOXG1-silenced or overexpressing human HCC cell lines. Immunoprecipitation and chromatin immunoprecipitation assays were performed to investigate the interaction of FOXG1, β-catenin, TCF4 and the effect on Wnt target-gene promoters. In human HCC, the level of FOXG1 progressively increased from surrounding non tumorous livers to HCC, reaching the highest levels in metastatic HCC. Furthermore, expression levels of FOXG1 directly correlated with cancer cell epithelial-mesenchymal transition (EMT) phenotype. In FOXG1-overexpressing cells, FOXG1 promotes the stabilization and nuclear accumulation of β-catenin by directly binding to β-catenin and it associates with the lymphoid enhancer factor/T cell factor proteins (LEF/TCFs) on Wnt responsive enhancers (WREs) in chromatin. The results show that FOXG1 plays a key role in mediating cancer cell metastasis through the Wnt/β-catenin pathway in HCC cells and predicts HCC prognosis after surgery. Targeting FOXG1 may provide a new approach for therapeutic treatment in the future.

中文翻译：

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Forkhead box (FOX) G1 通过形成 T 细胞因子 4/Beta-catenin/FOXG1 复合物激活 Wnt 信号，促进肝细胞癌上皮-间质转化。

叉头框 G1 (FOXG1) 是 Fox 转录因子家族的成员，参与多种癌症的调节。然而，FOXG1 在肝细胞癌发生中的作用尚不清楚。本研究旨在探讨FOXG1在肝细胞癌（HCC）肿瘤转移中的生物学功能、潜在机制及其临床意义。通过免疫组织化学和实时 PCR 分析测定 HCC 细胞系和人类 HCC 样本中的 FOXG1 水平。在 FOXG1 沉默或过表达的人 HCC 细胞系中，体外和体内研究了 FOXG1 对癌细胞侵袭和转移的影响。进行免疫沉淀和染色质免疫沉淀测定，以研究 FOXG1、β-连环蛋白、TCF4 的相互作用以及对 Wnt 靶基因启动子的影响。在人类肝癌中，FOXG1的水平从周围非肿瘤肝脏到HCC逐渐升高，在转移性HCC中达到最高水平。此外，FOXG1 的表达水平与癌细胞上皮间质转化 (EMT) 表型直接相关。在 FOXG1 过表达细胞中，FOXG1 通过直接与 β-catenin 结合促进 β-catenin 的稳定和核积累，并与 Wnt 反应增强子 (WRE) 上的淋巴增强因子/T 细胞因子蛋白 (LEF/TCF) 结合。染色质。结果表明，FOXG1在HCC细胞中通过Wnt/β-catenin通路介导癌细胞转移中发挥关键作用，并预测HCC术后预后。靶向FOXG1可能为未来的治疗提供新的方法。