Hypoxia-inducible factor-1 alpha and Wnt/beta-catenin signaling pathways promote the invasion of hypoxic gastric cancer cells

摘要

The present study aimed to examine the association between hypoxia-inducible factor (HIF)-1 alpha and the Wnt/beta-catenin signaling pathway in a hypoxic environment. The study also aimed to explore the possible mechanisms underlying the invasion of hypoxic gastric cancer cells in vitro and in vivo. The pcDNA (TM) 6.2-GW/EmGFP-miR-beta-catenin plasmid was transfected into SGC-7901 gastric cancer cells, resulting in cells with stable suppression of beta-catenin expression. The biological characteristics of the control, liposome, negative control, beta-catenin knockdown, hypoxia and hypoxia beta-catenin knockdown groups were tested using an invasion assay. The differences in the invasive capacity of the control, negative control and liposome groups were not statistically significant. However, the hypoxia group demonstrated a significantly enhanced invasive capacity, as compared with that in the control group (P<0.05). In the hypoxia beta-catenin knockdown group, reduced cell penetration and diminished invasive behavior was observed (P<0.05). In the hypoxia and double (chemical + physical) hypoxia groups, HIF-1 alpha, beta-catenin, urokinase-type plasminogen activator (uPA) and matrix metalloproteinase (MMP-7) protein and mRNA expression levels were elevated. In response to knockdown of beta-catenin expression, HIF-1 alpha, beta-catenin, uPA and MMP-7 protein as well as mRNA expression levels were significantly reduced in the hypoxia beta-catenin knockdown and the double hypoxia beta-catenin knockdown groups. In an in vivo experiment, the growth rate of xenograft tumors of hypoxic and control cells was high alongside increased HIF-1 alpha, beta-catenin, uPA and MMP-7 levels according to western blot and immunohistochemical analyses, while growth and protein levels of tumors from hypoxic beta-catenin knockdown cells were significantly lower and those of beta-catenin knockdown cells were lowest. In conclusion, these results suggested that HIF-1 alpha activation was able to regulate the Wnt/beta-catenin pathway, and that HIF-1 alpha may be controlled by the Wnt/beta-catenin pathway. A potential mechanism underlying SGC-7901 tumorigenicity is the activation of the Wnt/beta-catenin signaling pathway, which activates uPA and MMP-7 expression and contributes to the enhanced invasion of hypoxic cancer cells.