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

Ye,Jianwen; Chen,Kunlun; Qi,Lei; Li,Renfeng; Tang,Hongwei; Zhou,Chuang; Zhai,Wenlong

doi:10.3892/or.2018.6751

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

Authors:
- Jianwen Ye
- Kunlun Chen
- Lei Qi
- Renfeng Li
- Hongwei Tang
- Chuang Zhou
- Wenlong Zhai
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Affiliations: Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China, Department of Endocrinology and Metabolism, The Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China, Key Laboratory of Digestive Organ Transplantation of Henan Province; Open and Key Laboratory of Hepatobiliary and Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities; Zhengzhou Key Laboratory of Hepatobiliary and Pancreatic Disease and Organ Transplantation, Zhengzhou, Henan 450052, P.R. China
Published online on: September 28, 2018 https://doi.org/10.3892/or.2018.6751
Pages: 3501-3510

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Abstract

Hypoxia plays a crucial role in cancer development and progression. Overexpression of hypoxia-inducible factor-1α (HIF‑1α) 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‑1α, 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‑1α was significantly upregulated in GBC tissues. HIF‑1α overexpression was closely associated with lymph node metastasis and tumor‑lymph node‑metastasis (TNM) stages. HIF‑1α 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‑1α (siHIF‑1α) and 2‑methoxyestradiol. Further experiments demonstrated that metformin inhibited hypoxia‑induced migration via HIF‑1α/VEGF in vitro. In addition, metformin suppressed GBC growth and downregulated the expression of HIF‑1α and VEGF in a GBC‑SD cell xenograft model. Taken together, these results suggest that HIF‑1α may contribute to tumor migration via the overexpression of VEGF in GBC, while metformin is able to inhibit tumor migration by targeting the HIF‑1α/VEGF pathway.

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