Clinical relevance and therapeutic potential of angiopoietin-like protein 4 in hepatocellular carcinoma

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• 作者：Kevin Tak-Pan Ng (1)
  Aimin Xu (2)
  Qiao Cheng (1)
  Dong Yong Guo (1)
  Zophia Xue-Hui Lim (1)
  Chris Kin-Wai Sun (1)
  Jeffrey Hon-Sing Fung (1)
  Ronnie Tung-Ping Poon (1)
  Sheung Tat Fan (1)
  Chung Mau Lo (1)
  Kwan Man (1)
  
  1. 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
  2. Department of Medicine ; 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
  
• 关键词：Hepatocellular carcinoma ; Angiopoietin ; like 4 ; Angiogenesis ; Metastasis ; Therapeutic
• 刊名：Molecular Cancer
• 出版年：2014
• 出版时间：December 2014
• 年：2014
• 卷：13
• 期：1
• 全文大小：4,132 KB
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• 刊物主题：Cancer Research; Oncology;
• 出版者：BioMed Central
• ISSN：1476-4598

文摘

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. Conclusion ANGPTL4 is a diagnostic and prognostic biomarker for HCC patients and a potential therapeutic agent to suppress HCC growth, angiogenesis and metastasis.