Clinicopathological and prognostic significance of serum and tissue Dickkopf-1 levels in human hepatocellular carcinoma

Abstract

Background: Although Dickkopf-1 (DKK1) is known to be a negative regulator of the Wnt/β-catenin pathway, it has been recently found to be upregulated in cancers. Aims:: We investigated the clinical and prognostic significance of both serum and transcript DKK1 and its functional roles in human hepatocellular carcinoma (HCC). Methods:: We evaluated the expression level of DKK1 in both tissue and serum samples from patients with HCC using GeneChip microarray and real-time-quantitative PCR and sandwich ELISA system respectively. The clinicopathological and prognostic significance of serum and tissue DKK1 levels was examined. Functional characterization of DKK1 with regard to cell migration, invasion and tumour growth was performed. Results:: Both DKK1 transcript and serum protein were upregulated in a stepwise manner in human HCCs. Its transcript levels were associated with more aggressive tumour behaviour, in terms of venous invasion (P = 0.003), advanced tumour stage (P = 0.003). DKK1 transcript correlated with shorter overall (P = 0.006) and disease-free survival (P = 0.012), and higher serum DKK1 levels correlated with shorter disease-free survival (P = 0.046). Knockdown of DKK1 significantly reduced both migratory and invasive abilities of HCC cells, whereas overexpression of DKK1 enhanced the tumour formation efficiency and tumour growth in vivo. Conclusions:: Serum and tissue DKK1 levels increased in a stepwise manner in multistep hepatocarcinogenesis and had prognostic significance. DKK1 plays a functional role in cell migration, invasion and tumour growth. © 2011 John Wiley & Sons A/S.