FOXA2 suppresses the metastasis of hepatocellular carcinoma partially through matrix metalloproteinase-9 inhibition

The forkhead box transcription factor A2 (FOXA2) is a member of the hepatocyte nuclear factor family and plays an important role in liver development and metabolic homeostasis, but its role in the metastasis of hepatocellular carcinoma (HCC) has not been evaluated. In this study, we found that the e...

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Published in:Carcinogenesis (New York) 2014-11, Vol.35 (11), p.2576-2583
Main Authors: Wang, Jian, Zhu, Chang-Peng, Hu, Ping-Fang, Qian, Hui, Ning, Bei-Fang, Zhang, Qing, Chen, Fei, Liu, Jiao, Shi, Bin, Zhang, Xin, Xie, Wei-Fen
Format: Article
Language:English
Subjects:
Animals
Carcinoma, Hepatocellular - genetics
Carcinoma, Hepatocellular - pathology
Epithelial-Mesenchymal Transition - genetics
Gene Expression Regulation, Neoplastic
Hep G2 Cells
Hepatocyte Nuclear Factor 3-beta - biosynthesis
Hepatocyte Nuclear Factor 3-beta - genetics
Humans
Liver Neoplasms - genetics
Matrix Metalloproteinase 2 - biosynthesis
Matrix Metalloproteinase 2 - genetics
Matrix Metalloproteinase 9 - genetics
Mice
Neoplasm Invasiveness - genetics
Neoplasm Metastasis
RNA, Small Interfering
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Summary:The forkhead box transcription factor A2 (FOXA2) is a member of the hepatocyte nuclear factor family and plays an important role in liver development and metabolic homeostasis, but its role in the metastasis of hepatocellular carcinoma (HCC) has not been evaluated. In this study, we found that the expression of FOXA2 was decreased in 68.1% (49/72) of human HCC tissues compared with their paired non-cancerous adjacent tissues. Clinicopathological analysis revealed that reduced FOXA2 expression was correlated with aggressive characteristics (venous invasion, poor differentiation, high tumor node metastasis grade). FOXA2 level was even lower in portal vein tumor thrombus compared with primary tumor tissues and correlated with epithelial-mesenchymal transition in HCC cells. Overexpression of FOXA2 inhibited migration and invasion of Focus cells, whereas knockdown of FOXA2 in HepG2 showed the opposite effect. Moreover, upregulation of FOXA2 suppressed HCC metastasis to bone, brain and lung in two distinct mouse models. Finally, we proved that FOXA2 repressed the transcription of matrix metalloproteinase (MMP)-9 and exerted its antimetastasis effect partially through downregulation of MMP-9. In conclusion, our findings indicate that FOXA2 plays a critical role in HCC metastasis and may serve as a novel therapeutic target for HCC.
ISSN:0143-3334
1460-2180
DOI:10.1093/carcin/bgu180