High expression of Dickkopf-related protein 1 is related to lymphatic metastasis and indicates poor prognosis in intrahepatic cholangiocarcinoma patients after surgery

Authors

  • Ruo-Yu Shi MD,

    1. Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
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    • The first 2 authors contributed equally to this manuscript.

  • Xin-Rong Yang MD,

    1. Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
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    • The first 2 authors contributed equally to this manuscript.

  • Qiu-Jin Shen PhD,

    1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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  • Liu-Xiao Yang MD,

    1. Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
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  • Yang Xu MD,

    1. Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
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  • Shuang-Jian Qiu MD,

    1. Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
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  • Yun-Fan Sun MD,

    1. Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
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  • Xin Zhang MD,

    1. Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
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  • Zheng Wang MD,

    1. Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
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  • Kai Zhu MD,

    1. Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
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  • Wen-Xin Qin PhD,

    1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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  • Zhao-You Tang MD,

    1. Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
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  • Jia Fan MD, PhD,

    Corresponding author
    1. Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
    2. Institute of Biomedical Sciences, Fudan University, Shanghai, China
    • Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai 200032, China
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    • Fax: (011) 86 21-64037181

  • Jian Zhou MD, PhD

    Corresponding author
    1. Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China
    2. Institute of Biomedical Sciences, Fudan University, Shanghai, China
    • Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai 200032, China
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Abstract

BACKGROUND:

Dickkopf-related protein 1 (DKK1) has been reported involved in metastasis and invasion in several tumors. This study sought to investigate the prognostic value of DKK1 in intrahepatic cholangiocarcinoma (ICC) and its role in promoting ICC metastasis.

METHODS:

Tissue microarrays of 138 ICC patient samples were employed to detect DKK1, vascular endothelial growth factor C (VEGF-C), and matrix metalloproteinase 9 (MMP9) expression using immunohistochemistry. The prognostic significances were assessed by Kaplan-Meier survival estimates. DKK1 expression was measured in an ICC cell line (HCCC-9810) and ICC tissues by immunofluorescence assay, quantitative real-time polymerase chain reaction, and western blot. Serum levels of DKK1 from 37 ICC patients were tested by enzyme-linked immunosorbent assay. The role of DKK1 in proliferation, migration, invasion, and gene expression regulation was assessed by DKK1 depletion using small interfering RNA.

RESULTS:

Multivariate analyses revealed that DKK1 was an unfavorable predictor for overall survival and time to recurrence. The prognostic significance was retained in ICC patients with low recurrence risk (P < .05). DKK1 expression was elevated in an ICC cell line, tumor samples, and patient sera. High levels of DKK1 in ICC tissues correlated with elevated MMP9, VEGF-C, and metastasis of hepatic hilar lymph nodes. DKK1 depletion caused a decrease in cell migration and invasiveness, and down-regulation of MMP9 and VEGF-C expression.

CONCLUSIONS:

DKK1 is a novel prognostic biomarker for ICC, and it enhances tumor cell invasion and promotes lymph node metastasis of ICC through the induction of MMP9 and VEGF-C. DKK1 may be a potential therapeutic target for ICC. Cancer 2013. © 2012 American Cancer Society.

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