Dickkopf-1 expression as a marker for predicting clinical outcome in esophageal squamous cell carcinoma.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Makino
Tomoki
T
Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
Yamasaki
Makoto
M
Takemasa
Ichiro
I
Takeno
Atsushi
A
Nakamura
Yurika
Y
Miyata
Hiroshi
H
Takiguchi
Shuji
S
Fujiwara
Yoshiyuki
Y
Matsuura
Nariaki
N
Mori
Masaki
M
Doki
Yuichiro
Y
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000096:biosynthesis*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000401:mortality / Q000601:surgery; D004938:Esophageal Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000601:surgery; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome
D014408:Biomarkers, Tumor; C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins