The first 2 authors contributed equally to this manuscript.
High expression of Dickkopf-related protein 1 is related to lymphatic metastasis and indicates poor prognosis in intrahepatic cholangiocarcinoma patients after surgery
Article first published online: 6 NOV 2012
Copyright © 2012 American Cancer Society
Volume 119, Issue 5, pages 993–1003, 1 March 2013
How to Cite
Shi, R.-Y., Yang, X.-R., Shen, Q.-J., Yang, L.-X., Xu, Y., Qiu, S.-J., Sun, Y.-F., Zhang, X., Wang, Z., Zhu, K., Qin, W.-X., Tang, Z.-Y., Fan, J. and Zhou, J. (2013), High expression of Dickkopf-related protein 1 is related to lymphatic metastasis and indicates poor prognosis in intrahepatic cholangiocarcinoma patients after surgery. Cancer, 119: 993–1003. doi: 10.1002/cncr.27788
- Issue published online: 19 FEB 2013
- Article first published online: 6 NOV 2012
- Manuscript Accepted: 17 JUL 2012
- Manuscript Revised: 7 JUN 2012
- Manuscript Received: 6 MAR 2012
- Dickkopf-related protein 1;
- intrahepatic cholangiocarcinoma;
- lymphatic metastasis;
- vascular endothelial growth factor C;
- matrix metalloproteinase 9
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.
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.
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.
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.