title: Overexpression of hepatocyte nuclear factor 4α in human mesenchymal stem cells suppresses hepatocellular carcinoma development through Wnt/β-catenin signaling pathway downregulation.
abstract: Mesenchymal stem cells (MSCs) hold promise as cellular vehicles for the delivery of therapeutic gene products because they can be isolated, expanded, and genetically modified in vitro and possess tumor-oriented homing capacity in vivo. (1) Hepatocyte nuclear factor 4α (HNF4α) is a dominant transcriptional regulator of hepatocyte differentiation and hepatocellular carcinogenesis (HCC). (2,3) We have previously demonstrated that overexpression of HNF4α activates various hepatic-specific genes and enhances MSC differentiation. (4) However, the extent that overexpression of HNF4α in MSCs influences HCC progression has yet to be examined. Here we sought to investigate what effect MSCs overexpressing HNF4α (MSC-HNF4α) have on human hepatoma cells in vitro and in vivo. Conditioned medium collected from in vitro MSC-HNF4α cultures significantly inhibited hepatoma cell growth and metastasis compared with controls. Additionally, nude mice administered MSC-HNF4α exhibited significantly smaller tumors compared with controls in vivo. Immunoblot analysis of HCC cells treated with MSC-HNF4α displayed downregulated β-catenin, cyclinD1, c-Myc, MMP2 and MMP9. Taken together, our results demonstrate that MSC-HNF4α inhibits HCC progression by reducing hepatoma cell growth and metastasis through downregulation of the Wnt/β-catenin signaling pathway.
authors.affiliation: a Department of Liver Surgery , RenJi Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai , China.|b Department of General Surgery , Nanjing Hospital Affiliated to Nanjing Medical University , Nanjing , China.
authors.forename: Ning
authors.initials: N
authors.lastname: Wu
authors.affiliation: c ZunYi Medical university , ZunYi , China.
authors.forename: Yu-Ling
authors.initials: YL
authors.lastname: Zhang
authors.affiliation: b Department of General Surgery , Nanjing Hospital Affiliated to Nanjing Medical University , Nanjing , China.
authors.forename: Hai-Tian
authors.initials: HT
authors.lastname: Wang
authors.affiliation: a Department of Liver Surgery , RenJi Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai , China.
authors.forename: Da-Wei
authors.initials: DW
authors.lastname: Li
authors.affiliation: a Department of Liver Surgery , RenJi Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai , China.
authors.forename: Hui-Juan
authors.initials: HJ
authors.lastname: Dai
authors.affiliation: a Department of Liver Surgery , RenJi Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai , China.
authors.forename: Qi-Qi
authors.initials: QQ
authors.lastname: Zhang
authors.affiliation: a Department of Liver Surgery , RenJi Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai , China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: b Department of General Surgery , Nanjing Hospital Affiliated to Nanjing Medical University , Nanjing , China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Ma
authors.affiliation: a Department of Liver Surgery , RenJi Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai , China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xia
authors.affiliation: b Department of General Surgery , Nanjing Hospital Affiliated to Nanjing Medical University , Nanjing , China.
authors.forename: Jian-Min
authors.initials: JM
authors.lastname: Bian
authors.affiliation: a Department of Liver Surgery , RenJi Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai , China.
authors.forename: Hua-Lian
authors.initials: HL
authors.lastname: Hang
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation; D015536:Down-Regulation; D051536:Hepatocyte Nuclear Factors / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D014162:Transfection; D060449:Wnt Signaling Pathway / Q000235:genetics*
chemical_list: D051536:Hepatocyte Nuclear Factors
keywords: Gene therapy; Wnt/β-catenin signaling; hepatocyte nuclear factor 4α; hepatoma; mesenchymal stem cells