The regulatory mechanism and biological significance of the Snail-miR590-VEGFR-NRP1 axis in the angiogenesis, growth and metastasis of gastric cancer

Abstract

Vascular endothelial growth factor receptor (VEGFR) and neuropilins (NRPs), a co-receptor of VEGF, play a key role in the formation and development of blood vessels and in tumour growth and metastasis. However, whether VEGFR1/2 and NRP1 are regulated by the same upstream mechanism is unclear, especially in gastric cancer. We used prediction tools to detect miRNAs that may simultaneously regulate VEGFR1/2 and NRP1, and we finally determined that miR-590 can simultaneously regulate VEGFR1/2 and NRP1 in gastric cancer. We discovered that miR-590 was downregulated in gastric cancer tissues and cell lines, and this was related to the dysregulation of the transcription factor SNAIL. In addition, the overexpression of miR-590 inhibits the migration, invasion, proliferation and D-MVA levels of gastric cancer cells in vivo and in vitro by targeting VEGFR1/2 and NRP1. We also demonstrated that miR-590 may be a useful marker for the prognosis of gastric cancer with Kaplan–Meier survival analysis. Since the epithelial-to-mesenchymal transition (EMT) is an important mechanism of tumour invasion and metastasis and VEGFR1/2 and NRP1 can promote the occurrence of EMT, we speculated that miR-590 can regulate the occurrence of EMT. Immunoblot and immunofluorescence analyses confirmed that the overexpression of miR-590 can inhibit the EMT in gastric cancer cells. Since SNAIL is also a mesenchymal marker, our results revealed a new, positive feedback loop. As a transcription factor, SNAIL inhibits the expression of miR-590, thereby upregulating the expression levels of NRP1 and VEGFR1/2; this leads to the development of EMT in gastric cancer and the upregulation of SNAIL.