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

• Published in: Journal of hepatology 2009-05, Vol.50 (5), p.948-957
• Main Authors: Yu, Bin, Yang, Xinrong, Xu, Yang, Yao, Genfu, Shu, Huiqun, Lin, Biaoyang, Hood, Leroy, Wang, Hongyang, Yang, Shengli, Gu, Jianren, Fan, Jia, Qin, Wenxin
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; beta Catenin - genetics; beta Catenin - metabolism; Biological and medical sciences; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Carcinoma, Hepatocellular - diagnosis; Carcinoma, Hepatocellular - metabolism; Cell Line, Tumor; Cell Nucleus - metabolism; Cytoplasm - metabolism; DKK1; DNA, Neoplasm - genetics; Female; Gastroenterology and Hepatology; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Regulation, Neoplastic; HCC; Humans; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Kaplan-Meier Estimate; Liver Neoplasms - diagnosis; Liver Neoplasms - metabolism; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Middle Aged; Oligonucleotide Array Sequence Analysis; Predictive Value of Tests; Predictor; Prognosis; Tumor tissue microarray; Tumors; β-Catenin
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2008.11.020

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 β-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 β-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 β-catenin in HCC cell lines, and DKK1 overexpression correlated with β-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 β-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 β-catenin, is a novel prognostic predictor for HCC patients.