Upregulation of nectin-4 is associated with ITGB1 and vasculogenic mimicry and may serve as a predictor of poor prognosis in colorectal cancer.

Abstract

Colorectal cancer (CRC) is one of the most common malignancies worldwide. Unlike endothelium-dependent vasculature, vasculogenic mimicry (VM) is an alternative type of blood supply in tumors that is frequently associated with poor patient outcome. Nectin-4 serves a vital role in the formation and maintenance of adherens junctions; integrin β-1 (ITGB1) promotes tumor invasion, metastasis and VM formation. In the present study, the analysis of nectin-4 mRNA expression in a database of The Cancer Genome Atlas (TCGA) was combined with that of another non-overlapping cohort of 68 patients with CRC. TCGA data were used to examine nectin-4 mRNA expression in CRC and its correlation with the clinicopathological features of patients. Data from the non-overlapping cohort of patients was used to determine nectin-4 and ITGB1 protein expression in CRC by immunohistochemical (IHC) staining. Cluster of differentiation 34/periodic acid-Schiff double staining was performed to validate the presence of VM formation. The association with, and significance of combining nectin-4, ITGB1 protein expression and VM formation for predicting patient prognosis was evaluated. The TCGA dataset demonstrated that nectin-4 mRNA was upregulated in CRC, which was significantly relate to lymph node metastasis (P=0.0017), distant metastasis (P=0.0045), and tumor-node-metastasis (TNM) stage (P=0.0015). Of the 68 patients analyzed by IHC staining, 48 (70.6%) were positive for nectin-4, 46 (67.6%) for ITGB1 and 17 (25%) for VM formation. Nectin-4 protein expression was associated with ITGB1 protein expression (P<0.01) and VM formation (P<0.05). Nectin-4, ITGB1 expression and VM formation were associated with distant metastasis stage (P<0.05) and TNM stage (P<0.05). Based on these findings it was concluded that nectin-4 was upregulated in CRC tissues compared with normal mucosal tissues, and was associated with ITGB1 expression and VM formation. Furthermore, nectin-4 and ITGB1 protein expression, together with VM formation may be used to predict poor prognosis in CRC.