Metformin suppresses hypoxia-induced migration via the HIF-1α/VEGF pathway in gallbladder cancer in vitro and in vivo

Hypoxia plays a crucial role in cancer development and progression. Overexpression of hypoxia-inducible factor-1 (HIF-1) has been demonstrated in a hypoxic microenvironment in various tumor types. Metformin has been identified as an antitumor drug in various tumor types. However, its role in cellular migration in a hypoxic microenvironment, and the associated regulatory mechanism, have yet to be fully elucidated. The present study aimed to investigate the clinical significance of HIF-1, and its biological role, in gallbladder cancer (GBC). Furthermore, the role of metformin in cellular migration, and its underlying mechanism in GBC, were also identified. Real-time quantitative polymerase chain reaction analysis and immunohistochemistry experiments revealed that HIF-1 was significantly upregulated in GBC tissues. HIF-1 overexpression was closely associated with lymph node metastasis and tumor-lymph node-metastasis (TNM) stages. HIF-1 was able to promote cell migration in a hypoxic microenvironment by overexpressing vascular endothelial growth factor (VEGF) in GBC-SD cells, an effect which was partly reversed by small-interfering RNA HIF-1 (siHIF-1) and 2-methoxyestradiol. Further experiments demonstrated that metformin inhibited hypoxia-induced migration via HIF-1/VEGF in vitro. In addition, metformin suppressed GBC growth and downregulated the expression of HIF-1 and VEGF in a GBC-SD cell xenograft model. Taken together, these results suggest that HIF-1 may contribute to tumor migration via the overexpression of VEGF in GBC, while metformin is able to inhibit tumor migration by targeting the HIF-1/VEGF pathway.