Netrin-1 interference potentiates epithelial-to-mesenchymal transition through the PI3K/AKT pathway under the hypoxic microenvironment conditions of non-small cell lung cancer

Netrin-1 is overexpressed in several types of cancer. However, whether netrin-1 can potentiate hypoxia-induced tumor progression in lung cancer has not been reported to date. Thus, the objective of the present study was to investigate whether netrin-1 regulates cancer cell migration and invasion under hypoxic conditions in lung cancer and explore the underlying mechanism. A three-dimensional microfluidic chip was used to observe real-time changes in cancer cells, and cobalt chloride (CoCl2) was used to simulate a hypoxic microenvironment. Netrin-1 siRNA was employed in the A549 and PC9 cell lines to downregulate the expression of netrin-1. Microfluidic chip, wound healing and Transwell assays were used to examine cell migration and invasion. The expression levels of E-cadherin and vimentin were detected by western blotting. The data demonstrated that netrin-1 mediated epithelial-to-mesenchymal transition (EMT) of A549 and PC9 cells in vitro, which may be associated with the phosphoinositide 3 kinase/AKT pathway. This effect of netrin-1 on the EMT was not observed in the normoxic microenvironment. In this retrospective study, netrin-1 concentrations were evaluated in serum obtained from patients with non-small cell lung cancer (NSCLC) and compared with healthy control samples by quantitative enzyme-linked immunosorbent analysis. The serum concentration of netrin-1 was found to be significantly higher in NSCLC patients compared with that in healthy donors. Taken together, the findings of the present study highlight a novel role for netrin-1 in tumor development under hypoxia in NSCLC and provide further evidence for the use of netrin-1 as a therapeutic target.