Dickkopf-1 Expression as a Marker for Predicting Clinical Outcome in Esophageal Squamous Cell Carcinoma

Dickkopf-1 (DKK1) is the inhibitor of the canonical Wnt signaling pathway, however it is highly transactivated in various cancers, suggesting the presence of unknown mechanism. Its implication in human esophageal squamous cell carcinoma (ESCC) has not been sufficiently investigated. We evaluated DKK1 protein expression in resected specimens from 170 patients with ESCC by immunohistochemistry. Tumors were categorized as positive or negative for DKK1. The relationships between DKK1 expression in ESCC and various clinicopathological parameters and prognosis (disease-free survival; DFS) were analyzed separately. Immunohistochemically, 72 (42.4%) tumors were DKK1 positive while no significant staining was observed in the normal squamous epithelium except for few basal cells. There was no significant relationship between DKK1 expression in ESCC and any of the clinicopathological parameters tested in this study. Patients with DKK1-positive tumors had poorer DFS than those with negative ESCC (5-year DFS; 31.5% versus 53.6%, P = 0.0062). Univariate analysis showed a significant relationship between pT [hazard ratio (HR) = 2.944, 95% confidence interval (CI) = 1.713-5.059, P < 0.0001], number of pN (HR = 2.836, 95% CI = 1.866-4.309, P < 0.0001), lymphatic invasion (HR = 2.892, 95% CI = 1.336-6.262, P = 0.0070), and DKK1 expression (HR = 1.763, 95% CI = 1.167-2.663, P = 0.0071) and DFS. Multivariate analysis including the above four parameters identified pT (HR = 2.053, 95% CI = 1.157-3.645, P = 0.0140), pN number (HR = 2.107, 95% CI = 1.362-3.260, P = 0.0008), and DKK1 expression (HR = 1.813, 95% CI = 1.195-2.751, P = 0.0052) as independent and significant prognostic factors for DFS. Our data suggest the usefulness of DKK1 as a novel predictor of poor prognosis of patients with ESCC after curative resection and also as a therapeutic target for future tailored therapies against ESCC.