Delta-like ligand 4: A predictor of poor prognosis in clear cell renal cell carcinoma

Delta-like ligand 4 (D114)-Notch signaling is important in tumor angiogenesis; however, the prognostic value of D114 detection in patients with clear cell renal cell carcinoma (CCRCC) remains unclear. The present study aimed to determine whether the presence of high D114 expression levels was correlated with poor prognosis in CCRCC following curative resection. The D114 expression levels in four paired samples of CCRCC tissues and adjacent normal renal tissues were assayed by western blotting. Surgical specimens comprised 121 CCRCC tissue samples and 65 normal renal tissue samples, obtained from patients with CCRCC. The specimens were immunohistochemically assessed to determine D114 and vascular endothelial growth factor receptor 2 (VEGFR-2) expression levels. The prognostic significance of D114 expression levels was evaluated by the Kaplan-Meier method and Cox regression analysis. The correlation between D114 expression levels and VEGFR-2 expression levels, tumor stage, tumor grade and metastasis, was examined by chi(2) test and multivariate logistic regression. As determined by the western blotting results, D114 protein expression levels were significantly increased in CCRCC tissues compared with those in adjacent non-cancerous tissues. From the analysis of the surgical specimens, 53 (43.8%) CCRCC patients exhibited immunohistochemically high D114 expression levels and 68 (56.2%) patients exhibited low D114 expression levels. The survival curves revealed that the patients with high D114 expression levels had significantly shorter survival times than the patients with low D114 expression levels (P<0.0.01). Multivariate survival analysis demonstrated that the presence of high D114 expression levels was independently associated with reduced overall survival and progression-free survival times (P=0.021 and 0.034, respectively). A positive correlation was also identified between D114 and VEGFR-2 expression levels (P=0.001). In conclusion, the results show that the presence of high D114 expression levels was clearly associated with high VEGFR-2 expression levels, tumor grade, tumor stage and poor prognosis in CCRCC patients. Therefore, inhibition of D114 may exert potent growth inhibitory effects on tumors resistant to anti-VEGF therapies for CCRCC.