Abstract
BackgroundForkhead 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.MethodsLevels 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.ResultsIn 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.ConclusionsThe 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.
Highlights
Forkhead box G1 (FOXG1) is a member of the Fox transcription factor family involved in regulation of many cancers
FOXG1 was up-regulated in hepatocellular carcinoma (HCC) and associated with poor prognosis By analyzing the datasets from the GEO Publication Omnibus, we found the expression of FOXG1 was significantly up-regulated in adjacent non tumor tissue (ANT) and cirrhotic liver tissue (CIRR), with the highest level in HCC tissues (HCC) compared with healthy liver tissue (HEAL) (Fig. 1a)
FOXG1 expression was upregulated in 7 HCC cell lines compared with normal LO2 liver cells detected by qPCR and western blotting analysis (Fig. 1b and c)
Summary
Forkhead box G1 (FOXG1) is a member of the Fox transcription factor family involved in regulation of many cancers. 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. According to the 2018 cancer statistics report, the five-year relative survival rate for HCC patients is only 18%. Abnormal Wnt signal activation caused by genetic mutationis was responsible for 30% of hepatitis B virus-(HBV)-related HCC and involved in epithelial-mesenchymal transition (EMT), which is the main mechanism of tumor metastasis [3]. Aberrant Wnt/β-catenin activation has been reported in approximately 50% of all HCC [4]. Identifying alternative mechanisms and molecular factors for predicting tumor metastasis will help improve the overall clinical management of HCC patients
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