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

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

DKK1 promotes hepatocellular carcinoma cell migration and invasion through β-catenin/MMP7 signaling pathway

“…Numerous studies have shown that DKK1 was implicated in the control of various pathological and physiological processes, including adult hippocampal neurogenesis [5], osteoclastogenesis [6], tumor cell proliferation, survival, migration and invasion [7,8]. However, the role of DKK1 in tumor biology is controversial.…”

“…High expression of DKK1 has also been reported in breast and kidney cancers [13]. A recent research article showed that high expression of DKK1 is related to lymphatic metastasis and indicates poor prognosis in intrahepatic cholangiocarcinoma (ICC) patients after surgery, vice versa, depletion of DKK1 using small interfering RNA results in a decrease in ICC cell migration and invasion [8]. Taken together, all these findings suggest that DKK1 performs an oncogenic or a tumor-suppressing function depends on the cell type or context.…”

miR-191 Inhibition Induces Apoptosis Through Reactivating Secreted Frizzled-Related Protein-1 in Cholangiocarcinoma

“…CCA usually metastasize and cause relapse because it is commonly diagnosed in the advanced stage of the disease, and leads to poor prognosis [2][3][4]. Many studies have revealed that numerous genes are involved in CCA [5][6][7][8][9] and many therapeutic strategies have been developed to treat CCA [10][11][12]; however, the survival rate for CCA patients is still low [13].…”

Circulating Biomarkers for Cholangiocarcinoma

“…Other candidate serum markers that have been reported for the diagnosis of CCA include sperm-specific protein 411 [58], dickkopf-related protein 1 [59], and KL-6 mucin [60]. Nevertheless, larger validation studies are needed to confirm these findings and establish the potential markers clinically.…”