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High expression levels of putative hepatic stem/progenitor cell biomarkers related to tumour angiogenesis and poor prognosis of hepatocellular carcinoma
  1. Xin-Rong Yang1,
  2. Yang Xu1,
  3. Bin Yu2,
  4. Jian Zhou1,
  5. Shuang-Jian Qiu1,
  6. Guo-Ming Shi1,
  7. Bo-Heng Zhang1,
  8. Wei-Zhong Wu1,
  9. Ying-Hong Shi1,
  10. Bin Wu1,
  11. Guo-Huan Yang1,
  12. Yuan Ji1,
  13. Jia Fan1
  1. 1Liver Cancer Institute, Zhong Shan Hospital and Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis & Cancer Invasion, The Chinese Ministry of Education, Shanghai, PR China
  2. 2National Laboratory for Oncogenes and Related Genes, WHO Collaborating Center for Research on Cancer, Shanghai Cancer Institute, Shanghai, PR China
  1. Correspondence to Professor Jia Fan, Liver Cancer Institute & Zhong Shan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai 200032, PR China; jiafan99{at}


Background/aims To investigate the prognostic values of putative hepatic stem/progenitor cell (HSC/HPC) biomarkers in patients with hepatocellular carcinoma (HCC).

Methods Fourteen biomarkers related to HSCs/HPCs or tumour angiogenesis were assessed by qRT-PCR and then validated by tissue microarrays (TMAs) in three independent cohorts of patients with HCC undergoing curative resection (n=67, 314 and 73).

Results Most of the biomarkers were found to be overexpressed in patients with recurrent HCC by quantitative reverse transcription–PCR (qRT–PCR). The HSC/HPC biomarkers cytokeratin 19, ATP-binding cassette subfamily G member 2 (ABCG2), CD133, Nestin and CD44, and the markers of angiogenesis microvessel density (MVD, determined by CD34 immunostaining), vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF) were confirmed as significant predictors for overall survival (OS) and/or relapse-free survival (RFS) in TMA analysis. As compared with the low HSC/HPC profile group, patients with a high HSC/HPC profile who had higher VEGF levels (p=0.012) and MVD (p=0.030) in tumours had significantly lower OS and RFS (p<0.0001). Based on Cox regression, a simplified model including CD133, CD44, Nestin and MVD was constructed and confirmed as an independent predictor for OS (p<0.0001) and RFS (p<0.0001), regardless of α-fetoprotein level, tumour stage and recurrence time (p<0.0001 for all).

Conclusion High expression levels of HSC/HPC biomarkers are related to tumour angiogenesis and poor prognosis of HCC. The simplified model based on the HSC/HPC and tumour angiogenesis profile can be used to classify patients with HCC with a high risk of tumour recurrence after surgery.

  • Hepatic stem cells
  • hepatic progenitor cells
  • hepatocellular carcinoma
  • molecular pathology
  • prognosis
  • tumour angiogenesis

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  • Funding This study was supported in part by grants from the National Natural Science Foundation of China (no. 30873039), the National Key Sci-Tech Special Project of China (no. 2008ZX10002-022), Shanghai Science and Technology Development Funds (no. 07SP07003, 10QH1400500 and no. 07JC14010) and the National High Technology Research and Development Program of China (863 Program, no. 2007AA02Z479).

  • Competing interests None.

  • Ethics approval Ethics approval for the use of human subjects was obtained from the research ethics committee of Zhong Shan Hospital, and informed consent was obtained from each patient.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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