title: Recombinant adenovirus carrying the hepatocyte nuclear factor-1alpha gene inhibits hepatocellular carcinoma xenograft growth in mice.
abstract: Hepatocyte nuclear factor-1alpha (HNF1α) is one of the key transcription factors of the HNF family, which plays a critical role in hepatocyte differentiation. Substantial evidence has suggested that down-regulation of HNF1α may contribute to the development of hepatocellular carcinoma (HCC). Herein, human cancer cells and tumor-associated fibroblasts (TAFs) were isolated from human HCC tissues, respectively. A recombinant adenovirus carrying the HNF1α gene (AdHNF1α) was constructed to determine its effect on HCC in vitro and in vivo. Our results demonstrated that HCC cells and HCC tissues revealed reduced expression of HNF1α. Forced reexpression of HNF1α significantly suppressed the proliferation of HCC cells and TAFs and inhibited the clonogenic growth of hepatoma cells in vitro. In parallel, HNF1α overexpression reestablished the expression of certain liver-specific genes and microRNA 192 and 194 levels, with a resultant increase in p21 levels and induction of G(2)/M arrest. Additionally, AdHNF1α inhibited the expression of cluster of differentiation 133 and epithelial cell adhesion molecule and the signal pathways of the mammalian target of rapamycin and transforming growth factor beta/Smads. Furthermore, HNF1α abolished the tumorigenicity of hepatoma cells in vivo. Most interestingly, intratumoral injection of AdHNF1α significantly inhibited the growth of subcutaneous HCC xenografts in nude mice. Systemic delivery of AdHNF1α could eradicate the orthotopic liver HCC nodules in nonobese diabetic/severe combined immunodeficiency mice.
  
  
  CONCLUSIONS
  These results suggest that the potent inhibitive effect of HNF1α on HCC is attained by inducing the differentiation of hepatoma cells into mature hepatocytes and G(2)/M arrest. HNF1α might represent a novel, promising therapeutic agent for human HCC treatment. Our findings also encourage the evaluation of differentiation therapy for tumors of organs other than liver using their corresponding differentiation-determining transcription factor.
authors: Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors: Xin
authors: X
authors: Zeng
authors: Yong
authors: Y
authors: Lin
authors: Chuan
authors: C
authors: Yin
authors: Xin
authors: X
authors: Zhang
authors: Bei-Fang
authors: BF
authors: Ning
authors: Qing
authors: Q
authors: Zhang
authors: Jun-Ping
authors: JP
authors: Zhang
authors: Lei
authors: L
authors: Qiu
authors: Xiao-Ran
authors: XR
authors: Qin
authors: Yue-Xiang
authors: YX
authors: Chen
authors: Wei-Fen
authors: WF
authors: Xie
mesh_terms: D000071916:AC133 Antigen; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D000951:Antigens, Neoplasm / Q000096:biosynthesis; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology*; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D000071858:Epithelial Cell Adhesion Molecule; D006023:Glycoproteins / Q000096:biosynthesis; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000502:physiology; D009368:Neoplasm Transplantation; D010455:Peptides; D014183:Transplantation, Heterologous; D054462:p21-Activated Kinases / Q000378:metabolism
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; D006023:Glycoproteins; D051538:Hepatocyte Nuclear Factor 1-alpha; D035683:MicroRNAs; D010455:Peptides; D054462:p21-Activated Kinases