The expression of VEGF receptor genes is concurrently influenced by epigenetic gene silencing of the genes and VEGF activation

Vascular endothelial growth factor (VEGF) activates the VEGF-VEGF receptor (VEGFR) signaling pathway in angiogenesis. Some cancer cell lines show decreased expression of the two VEGFRs, Flt-1 and KDR, even though VEGF is uniformly expressed in cancer cell lines. Promoter methylation is a well-known cause of epigenetic gene silencing in cancer cells. Although VEGF, Flt-1 and KDR have typical CpG islands in their promoter regions, the epigenetic transcriptional alterations of these genes have not yet been described. The present study evaluated the epigenetic gene silencing of VEGF and VEGFR genes in cancer tissues. We also analyzed whether the epigenetic alterations of VEGFR genes influence VEGFR expression concurrently with VEGF activation in cancer tissues. All cancer tissues we tested showed no methylation of VEGF, and variable promoter hypermethylation of Flt-1 and KDR. The promoter hypermethylation of Flt-1 and KDR was correlated with decreasing expression of the respective genes. In contrast, an increase in VEGF expression was positively correlated with Flt-1 and KDR expression in primary cancer tissues. The opposing influences of promoter methylation of VEGFR and increased VEGF expression concurrently influence Flt-1 and KDR expression in stomach cancer, colon cancer and hepatocellular carcinoma. The findings we observed showed that the epigenetic alteration developing in VEGFR genes might be an important factor to concurrently modulate expressions of the genes in addition to VEGF stimulation in cancer tissues. The epigenetic silencing of VEGFR genes should be considered in the activation of VEGF-VEGFR signaling pathway in the cancer cells.