Serum dickkopf-1 (DKK-1) as a biomarker for the diagnosis of hepatocellular carcinoma

Abstract

Backgrounds & Aims: Dickkopf-1 (DKK-1) is a Wnt/β-catenin signaling pathway inhibitor. We investigated whether DKK-1 is related to progression in hepatocellular carcinoma (HCC) cells and HCC patients. Methods: In vitro reverse-transcription (RT)-PCR, wound healing assays, and invasion assays, and ELISAs of patient serum samples were employed. The diagnostic accuracy of the serum DKK-1 ELISA was assessed using receiver operating characteristic (ROC) curves and area under ROC (AUC) analyses.Results: RT-PCR showed high DKK-1 expression in Hep3B and low in 293 cells. Similarly, the secreted DKK-1 concentration in the culture media was high in Hep3B and low for 293 cells. Wound healing and invasion assay using 293, Huh7, and Hep3B cells showed that DKK-1 overexpression promoted cell migration and invasion, whereas DKK-1 knock-down inhibited them. When serum DKK-1 level was assessed in 370 participants (217 with HCC and 153 without), it was significantly higher in HCC patients than in control groups (median 1.48 vs. 0.90 ng/mL, P<0.001). The optimum DKK-1 cutoff level was 1.01 ng/mL (AUC=0.829; sensitivity 90.7%; specificity 62.0%). DKK-1 had a greater AUC in diagnosing HCC than alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) (AUC=0.829 vs. 0.794 and 0.815, respectively). When all three biomarkers were combined (DKK-1+AFP+DCP), they showed remarkably increased accuracy (AUC=0.952). Conclusion: DKK-1 might be a key regulator in HCC progression and a potential therapeutic target in HCC. In addition, serum DKK-1 could complement the diagnostic accuracy of AFP and DCP.