Alternative splicing variant of vascular endothelial growth factor-A is a critical prognostic factor in non-small cell lung cancer

Lung cancer is one of the most common malignant diseases in the world, and its prognosis is generally poor. Cancer and metastasis involve numerous biological steps, including angiogenesis in both the primary and metastatic sites. Although various molecules that are involved in both tumor neovascularization (angiogenesis) and invasion have been identified, little is known about how these molecules interact in cancerous microenvironments. We previously reported that the gene expressions of some factors associated with vascularization correlated with the prognosis of non-small cell lung cancer (NSCLC). In this study, we performed multivariate analysis of the mRNA levels of 10 selected genes [VEGF-A, VEGF121, VEGF165, VEGF189, S100A4, E-cadherin, Thrombospondin (TSP)-1, TSP-2, matrix metalloproteinase (MMP)-2, and MMP-9] in 130 NSCLC specimens using the real-time quantitative reverse transcription-polymerase chain reaction. Spearman's rank correlation test was used to determine the co-expression patterns. The analysis demonstrated highly significant co-expressions (P<0.0001) among the VEGF isoforms (VEGF-A, VEGF121, VEGF165, and VEGF189). We also analyzed the correlations among the prognosis, gene expressions, clinical factors (age and gender), and pathological features (histological types, TNM status, stages, lymphatic involvement, and venous involvement) using the Cox proportional hazards model. Multivariate analyses showed that only VEGF189 expression was an independent prognostic indicator (P=0.0252). The alternative splicing variant VEGF189, the cell binding isoform, plays a leading role in the progression of NSCLC.