title: FOXA2 suppresses the metastasis of hepatocellular carcinoma partially through matrix metalloproteinase-9 inhibition.
abstract: 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.
authors.affiliation: Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China and Department of Internal Medicine, Chinese PLA 531 Hospital, Tonghua 134000, Jilin, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine, Chinese PLA 531 Hospital, Tonghua 134000, Jilin, China.
authors.forename: Chang-Peng
authors.initials: CP
authors.lastname: Zhu
authors.affiliation: Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China and Department of Internal Medicine, Chinese PLA 531 Hospital, Tonghua 134000, Jilin, China.
authors.forename: Ping-Fang
authors.initials: PF
authors.lastname: Hu
authors.affiliation: Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China and Department of Internal Medicine, Chinese PLA 531 Hospital, Tonghua 134000, Jilin, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Qian
authors.affiliation: Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China and Department of Internal Medicine, Chinese PLA 531 Hospital, Tonghua 134000, Jilin, China.
authors.forename: Bei-Fang
authors.initials: BF
authors.lastname: Ning
authors.affiliation: Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China and Department of Internal Medicine, Chinese PLA 531 Hospital, Tonghua 134000, Jilin, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China and Department of Internal Medicine, Chinese PLA 531 Hospital, Tonghua 134000, Jilin, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Chen
authors.affiliation: Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China and Department of Internal Medicine, Chinese PLA 531 Hospital, Tonghua 134000, Jilin, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China and Department of Internal Medicine, Chinese PLA 531 Hospital, Tonghua 134000, Jilin, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Shi
authors.affiliation: Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China and Department of Internal Medicine, Chinese PLA 531 Hospital, Tonghua 134000, Jilin, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China and Department of Internal Medicine, Chinese PLA 531 Hospital, Tonghua 134000, Jilin, China weifenxie@medmail.com.cn.
authors.forename: Wei-Fen
authors.initials: WF
authors.lastname: Xie
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D051542:Hepatocyte Nuclear Factor 3-beta / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis; D034741:RNA, Small Interfering
chemical_list: C496502:FOXA2 protein, human; D034741:RNA, Small Interfering; D051542:Hepatocyte Nuclear Factor 3-beta; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9