Clinical relevance and therapeutic potential of angiopoietin-like protein 4 in hepatocellular carcinomaReportar como inadecuado

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Molecular Cancer

, 13:196

First Online: 22 August 2014Received: 17 February 2014Accepted: 19 August 2014DOI: 10.1186-1476-4598-13-196

Cite this article as: Ng, K.TP., Xu, A., Cheng, Q. et al. Mol Cancer 2014 13: 196. doi:10.1186-1476-4598-13-196


BackgroundDevelopment 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.

MethodsANGPTL4 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.

ResultsHCC 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.

ConclusionANGPTL4 is a diagnostic and prognostic biomarker for HCC patients and a potential therapeutic agent to suppress HCC growth, angiogenesis and metastasis.

KeywordsHepatocellular carcinoma Angiopoietin-like 4 Angiogenesis Metastasis Therapeutic AbbreviationsAFPAlpha fetoprotein

ANGPTL4Angiopoietin-like 4

CNVCopy number variation

HCCHepatocellular carcinoma

HSCHepatic stellate cell

MVDMicrovessel density

pTNMPathologic tumor-node-metastasis

qRT-PCRQuantitative reverse transcriptase polymerase chain reaction

ROCReceiver operating characteristic

SMASmooth muscle actin

TAMTumor-associated macrophages

TUNELTerminal deoxynucleotidyl transferase dUTP nick end labeling

VEGFVascular endothelial growth factor.

Electronic supplementary materialThe online version of this article doi:10.1186-1476-4598-13-196 contains supplementary material, which is available to authorized users.

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Autor: Kevin Tak-Pan Ng - Aimin Xu - Qiao Cheng - Dong Yong Guo - Zophia Xue-Hui Lim - Chris Kin-Wai Sun - Jeffrey Hon-Sing F


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