Serum level of DKK1 as a marker for predicting tumor recurrence of hepatocellular carcinoma

Abstract

Dickkopf-1 (DKK1), an inhibitor of Wnt/beta-catenin signaling pathway, is upregulated in various cancers including HCC. However, the clinical significance of serum DKK1 in hepatocellullar carcinoma (HCC) remains to be determined. The objective of this study was to investigate the clinical significance of DKK1 and its prognostic value in predicting survival and tumor recurrence in human HCC. Two independent cohorts with 217 and 100 pairs of tumors and corresponding nontumor livers were employed for microarray analysis and real time-quantitative PCR (qPCR), respectively, to investigate the DKK1 transcript levels in human HCC samples. The serum levels of DKK1 were determined in 50 patients with early HCC, 50 patients with advanced HCC, 50 patients with cirrhosis, 50 hepatitis B virus (HBV) carriers, and 30 HCC patients after liver resection, using sandwich ELISA system. Transcript level of DKK1 in the human HCCs was found to be significantly upregulated as compared with the corresponding nontumorous livers in both microarray (P < 0.001) and qPCR cohorts (P < 0.001). Increased expression of DKK1 was associated with advanced tumor stage (P < 0.001), venous infiltration (P < 0.001), high serum alpha-fetoprotein (AFP) level (P < 0.001). Higher level of DKK1 correlated with both poorer overall survival (P = 0.016) and tumor recurrence (P = 0.014). On the other hand, the serum DKK1 level in the group of HBV carriers without HCC (as control) was not significantly different from that of the cirrhosis group (P = 0.086). In contrast, the serum DKK1 level was significantly higher in patients with early HCC (P < 0.001) and advanced HCC (P < 0.001), as compared with the HBV carrier group. Furthermore, the serum DKK1 level in patients after liver resection was significantly reduced (P < 0.001). Higher serum DKK1 level was associated with tumor recurrence (P = 0.046). To conclude, our data have demonstrated that tissue and serum DKK1 levels were significantly and progressively elevated during HCC formation and progression. DKK1 has prognostic role in predicting overall survival and disease-free survival of HCC patients, and serum DKK1 is a potential biomarker for predicting tumor recurrence.