title: Elevated DLL4 expression is correlated with VEGF and predicts poor prognosis of nasopharyngeal carcinoma.
abstract: Delta-like ligand 4 (DLL4), one of the transmembranous Notch ligands, is upregulated at the site of tumor growth, particularly during tumor angiogenesis. Expression pattern of DLL4 in nasopharyngeal carcinoma (NPC) and the clinical and prognostic significance remain unclear. In this study, immunohistochemical analysis (IHC) was used to examine the protein level of DLL4 in NPC tissues from two independent cohorts. In the testing cohort (311 cases), we applied the X-tile program software able to assess the optimal cutoff points for biomarkers in order to accurately classify patients according to clinical outcome. In the validation cohort (113 cases), the cutoff score derived from X-title analysis was investigated to determine the association of DLL4 expression with disease-specific survival (DFS). Our results showed that high expression of DLL4 was observed in 134 of 313 (42.8 %) in the testing cohort and 58 of 113 (43.6 %) in the validation cohort. High expression of DLL4 independently predicted poorer disease-specific survival, as evidenced by univariate and multivariate analysis (P < 0.05). Moreover, DLL4 expression was significantly elevated in distant NPC metastases relative to primary NPC tumors (P = 0.001). Importantly, we found a significant positive relationship between DLL4 and vascular endothelial growth factor (VEGF) (P < 0.001). Patients with dual elevated DLL4 and VEGF expression displayed a significant overall survival disadvantage compared to those with dual low expression (P < 0.05). These findings provide evidence that high expression of DLL4 serves as an independent predictor of poor prognosis in NPC patients.
authors.affiliation: State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
authors.forename: Jia-Xing
authors.initials: JX
authors.lastname: Zhang
authors.forename: Man-Bo
authors.initials: MB
authors.lastname: Cai
authors.forename: Xiao-Pai
authors.initials: XP
authors.lastname: Wang
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Duan
authors.forename: Qiong
authors.initials: Q
authors.lastname: Shao
authors.forename: Zhu-Ting
authors.initials: ZT
authors.lastname: Tong
authors.forename: Ding-Zhun
authors.initials: DZ
authors.lastname: Liao
authors.forename: Yang-Yang
authors.initials: YY
authors.lastname: Li
authors.forename: Ma-Yan
authors.initials: MY
authors.lastname: Huang
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Zeng
authors.forename: Jian-Yong
authors.initials: JY
authors.lastname: Shao
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000032:analysis*; D015153:Blotting, Western; D002135:Calcium-Binding Proteins; D002277:Carcinoma; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D016016:Proportional Hazards Models; D012372:ROC Curve; D012189:Retrospective Studies; D012680:Sensitivity and Specificity; D046888:Tissue Array Analysis; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D042461:Vascular Endothelial Growth Factor A