DLL4 as a predictor of pelvic lymph node metastasis and a novel prognostic biomarker in patients with early-stage cervical cancer

Abstract

Delta-like ligand 4 (DLL4), one of the five Notch signaling ligands in mammals, has an important function in proliferation, invasion, metastasis, progression, and angiogenesis of malignancies. This study aimed to investigate DLL4 expression level in early-stage cervical carcinoma and to evaluate its clinical significance. We used fresh frozen and paraffin-embedded cervical cancer tissues to analyze DLL4 expression and its clinical significance. DLL4 expression at both mRNA and protein levels in cervical cancer tissues was significantly higher than that in normal cervical tissues. High DLL4 protein level was clearly correlated with high International Federation of Gynecology and Obstetrics (FIGO) stage (P = 0.044), lymphovascular space involvement (LVSI) (P = 0.015), pelvic lymph node metastasis (PLNM) (P = 0.001), and recurrence (P < 0.001). Univariate and multivariate logistic regression analyses demonstrated that DLL4 overexpression was strongly associated with lymph node metastasis (odds ratio, 2.790; 95 % CI, 1.344–5.791; P = 0.006). Moreover, survival analysis revealed that DLL4 expression was an independent factor of unfavorable overall survival (hazard ratio, 2.130; 95 % CI, 1.108–4.097; P = 0.023) and disease-free survival (hazard ratio, 1.965; 95 % CI, 1.085–3.560; P = 0.026) in patients with cervical cancer. Overall, our data indicate that high DLL4 expression predicts pelvic lymph node metastasis and poor survival in cervical cancer. Therefore, DLL4 may be a potential clinical diagnostic marker for patients with early-stage cervical cancer.