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Overexpression of Dickkopf-1 predicts poor prognosis for patients with hepatocellular carcinoma after orthotopic liver transplantation by promoting cancer metastasis and recurrence

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Abstract

Our previous data had shown that Dickkopf-1 (DKK1) combined with β-catenin was a novel prognostic predictor for hepatocellular carcinoma (HCC) patients. However, the role and mechanism of DKK1 in HCC recurrence or metastasis remain poorly understand. This study was to assess the role of DKK1 in tumor metastasis for patients with hepatocellular carcinoma after orthotopic liver transplantation (OLT). The expression of DKK1 protein was detected in hepatic cell lines, HCC cell lines, and HCC patients after OLT with different potential of metastasis. After DKK1 expression in the HCCLM3 cells was downregulated by siRNA-mediated approach, the role of DKK1 in cell invasion and metastasis was investigated. cDNA genechip was used to analyze the differential expressed genes related with DKK1 in two pairs of HCC cells. The prognostic significance of DKK1 was further assessed by Kaplan–Meier and Cox regression analyses in 148 HCC patients after OLT. The expression of DKK1 protein was higher in the high-invasive HCC cells and HCC patients of the disease recurrence group. With the downregulation of DKK1, HCCLM3 cells showed decreased aggressiveness in vitro and lower metastatic ability in vivo. DKK1 could regulate many genes involved in biological processes and pathways related with tumor progression. Furthermore, DKK1 overexpression correlated with tumor microvessel density in clinical HCC samples. Multivariate analysis revealed that DKK1 was an independent prognostic indicator for overall survival and cumulative recurrence in this cohort of HCC patients post-OLT. Collectively, overexpression of DKK1 was implicated in invasion/metastasis of HCC after OLT and DKK1 overexpression may be potential molecular therapeutic targets for liver cancer.

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Acknowledgments

This study was funded by the National Key Basic Research Program of China (2009CB521803), the National Key Sci-Tech Special Projects of Infectious Diseases (2012ZX10002011-004), the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), and the Project of the State Key Laboratory of Oncogenes and Related Genes (90-10-04).

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Medical College of Nantong University, Nantong, China

    Yan Huang, Fengbo Zhao, Xiufang Lv, Baoying Hu & Wenxin Qin

  2. Liver Cancer Institute, Zhong Shan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, China

    Xinrong Yang & Jia Fan

  3. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, No. 25/2200, Xietu Road, Shanghai, 200032, China

    Qiujin Shen, Bin Yu & Wenxin Qin

  4. Department of General Surgery, the Affiliated Hospital, Nantong University, Nantong, China

    Yan Huang & Zhiwei Wang

  5. Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, China

    Bin Yu

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  1. Yan Huang
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  2. Xinrong Yang
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  3. Fengbo Zhao
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  7. Baoying Hu
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  8. Bin Yu
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  9. Jia Fan
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  10. Wenxin Qin
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Corresponding authors

Correspondence to Jia Fan or Wenxin Qin.

Additional information

Yan Huang, Xinrong Yang and Fengbo Zhao have contributed equally to this work.

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Huang, Y., Yang, X., Zhao, F. et al. Overexpression of Dickkopf-1 predicts poor prognosis for patients with hepatocellular carcinoma after orthotopic liver transplantation by promoting cancer metastasis and recurrence. Med Oncol 31, 966 (2014). https://doi.org/10.1007/s12032-014-0966-8

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  • DOI: https://doi.org/10.1007/s12032-014-0966-8

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