Elevated expression of DKK1 is associated with cytoplasmic/nuclear beta-catenin accumulation and poor prognosis in hepatocellular carcinomas.

ABSTRACT

BACKGROUND/AIMS: To assess the value of Dickkopf-1 (DKK1) for predicting clinical outcome of human hepatocellular carcinoma (HCC) in patients with HCC. METHODS: Expression of DKK1 and beta-catenin was investigated in HCC cell lines using qRT-PCR, Western blotting and immunofluorescence. Tissue microarrays representing 314 HCC patients were used to determine the expression patterns of DKK1 and beta-catenin by immunohistochemistry, and prognostic significance was assessed by using Kaplan-Meier survival estimates and log-rank tests. RESULTS: The expression level of DKK1 was associated with the staining pattern of beta-catenin in HCC cell lines, and DKK1 overexpression correlated with beta-catenin cytoplasmic/nuclear accumulation in clinical HCC samples (P=0.011, correlation coefficient=0.144). High DKK1 expression predicted unfavorable prognosis in HCC patients, especially in early stage patients and those with normal AFP levels. In multivariate analyses, DKK1 was an independent predictor for overall survival (OS) (P=0.002) and disease-free survival (DFS) (P=0.002) of HCC patients. Furthermore, the HCC patients with high DKK1 expression and cytoplasmic/nuclear beta-catenin accumulation had very poor prognosis. CONCLUSIONS: Elevated expression of DKK1 is a critical event in patients with HCC that indicates poor clinical outcome. DKK1, alone or combined with beta-catenin, is a novel prognostic predictor for HCC patients.