title: Clinical relevance and therapeutic potential of angiopoietin-like protein 4 in hepatocellular carcinoma.
abstract: BACKGROUND
  Development of novel adjuvant therapy to eradicate tumor angiogenesis and metastasis is a pressing need for patients with advanced hepatocellular carcinoma (HCC). We aimed to investigate the clinical relevance and therapeutic potential of angiopoietin-like 4 (ANGPTL4) in HCC.
  
  
  METHODS
  ANGPTL4 mRNA levels in tumor and non-tumor liver tissues of HCC patients were analyzed to investigate its clinical relevance. The mechanisms of deregulation of ANGPTL4 in HCC were studied by copy number variation (CNV) and CpG methylation analyses. The orthotopic liver tumor nude mice model was applied using a human metastatic cell line. ANGPTL4-overexpressing adenovirus (Ad-ANGPTL4) was injected via portal vein to investigate its anti-tumorigenic and anti-metastatic potentials.
  
  
  RESULTS
  HCC tissues expressed significantly lower levels of ANGPTL4 mRNA than non-tumor tissues. The copy number of ANGPTL4 gene in tumor tissues was significantly lower than in non-tumor tissues of HCC patients. Higher frequency of methylation of CpG sites of ANGPTL4 promoter was detected in tumor tissues compared to non-tumor tissues. Downregulation of ANGPTL4 mRNA in HCC was significantly associated with advanced tumor stage, presence of venous infiltration, poor differentiation, higher AFP level, appearance of tumor recurrence, and poor postoperative overall and disease-free survivals of HCC patients. Treatment with Ad-ANGPTL4 significantly inhibited the in vivo tumor growth, invasiveness and metastasis by promoting tumoral apoptosis, inhibiting tumoral angiogenesis and motility, and suppressing tumor-favorable microenvironment. Moreover, administration of recombinant ANGPTL4 protein suppressed the motility of HCC cells and altered the secretion profile of cytokines from macrophages.
  
  
  CONCLUSIONS
  ANGPTL4 is a diagnostic and prognostic biomarker for HCC patients and a potential therapeutic agent to suppress HCC growth, angiogenesis and metastasis.
authors.forename: Kevin Tak-Pan
authors.initials: KT
authors.lastname: Ng
authors.forename: Aimin
authors.initials: A
authors.lastname: Xu
authors.forename: Qiao
authors.initials: Q
authors.lastname: Cheng
authors.forename: Dong Yong
authors.initials: DY
authors.lastname: Guo
authors.forename: Zophia Xue-Hui
authors.initials: ZX
authors.lastname: Lim
authors.forename: Chris Kin-Wai
authors.initials: CK
authors.lastname: Sun
authors.forename: Jeffrey Hon-Sing
authors.initials: JH
authors.lastname: Fung
authors.forename: Ronnie Tung-Ping
authors.initials: RT
authors.lastname: Poon
authors.forename: Sheung Tat
authors.initials: ST
authors.lastname: Fan
authors.forename: Chung Mau
authors.initials: CM
authors.lastname: Lo
authors.affiliation: Department of Surgery and Centre for Cancer Research, LKS Faculty of Medicine, The University of Hong Kong, Room L9-55, Li Ka Shing Faculty of Medicine Building, 21 Sassoon Road, Pokfulam, Hong Kong, SAR, China. kwanman@hku.hk.
authors.forename: Kwan
authors.initials: K
authors.lastname: Man
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D045744:Cell Line, Tumor; D018899:CpG Islands; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation
chemical_list: C474772:ANGPTL4 protein, human; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins