Cancer Management and Research (Apr 2021)

Nrf2/HO-1 Axis Regulates the Angiogenesis of Gastric Cancer via Targeting VEGF

  • Huang Y,
  • Yang Y,
  • Xu Y,
  • Ma Q,
  • Guo F,
  • Zhao Y,
  • Tao Y,
  • Li M,
  • Guo J

Journal volume & issue
Vol. Volume 13
pp. 3155 – 3169

Abstract

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Yunning Huang,1,* Yuanyuan Yang,2,* Yuanyi Xu,2,* Qian Ma,3,4,* Fengying Guo,2 Yuan Zhao,2 Yuejia Tao,2 Mengqi Li,2 Jiaxin Guo2 1Department of Gastrointestinal Surgery, The Affiliated People’s Hospital of Ningxia Medical University, Yinchuan City, Ningxia Province, 750001, People’s Republic of China; 2Department of Pathology, Ningxia Medical University, Yinchuan City, Ningxia Province, 750004, People’s Republic of China; 3College of Life Sciences, Ningxia University, Yinchuan City, Ningxia Province, 750021, People’s Republic of China; 4College of Basic Medicine, Ningxia Medical University, Yinchuan City, Ningxia Province, 750004, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yunning Huang; Yuanyi Xu Email [email protected]; [email protected]: Gastric cancer (GC) is one of the most fatal digestive tumors worldwide. Abnormal activation or accumulation of the nuclear factor-erythroid 2-related factor 2/heme oxygenase 1 (Nrf2/HO-1) axis is a malignant event in numerous solid tumors. However, its involvement in angiogenesis of GC remains unknown. This study investigated the role of the Nrf2/HO-1 axis in angiogenesis of GC.Methods: The expression of Nrf2, HO-1, and vascular endothelial growth factor (VEGF) in BGC-823 cells under hypoxia was analyzed using immunocytochemistry, immunofluorescence, Western blotting, and quantitative polymerase chain reaction. The effects of brusatol (Nrf2 inhibitor) and tert-butylhydroquinone (Nrf2 inducer) on these factors and angiogenesis were examined using immunofluorescence, Western blotting, quantitative polymerase chain reaction, and tube formation assay. Moreover, immunohistochemistry and Western blotting were used to determine these factors and microvessel density in tumor and normal tissues of tumor-bearing and tumor-free mice, respectively. Immunohistochemistry and Western blotting were employed to examine these factors and microvessel density in human paracancerous tissues, well-differentiated GC, and poorly differentiated GC. The correlations between Nrf2, HO-1, and VEGF gene expression in 375 patients with GC from The Cancer Genome Atlas cohort were analyzed.Results: The expression of Nrf2, HO-1, and VEGF was increased in hypoxic BGC-823 cells (P< 0.05). Although brusatol decreased their expression and angiogenesis (P< 0.05), tert-butylhydroquinone had the opposite effect (P< 0.05). Moreover, the expression of Nrf2, HO-1, and VEGF, and microvessel density in tumor tissues was higher than that recorded in normal tissues of nude mice (P< 0.05). Similarly, these parameters were low in paracancerous tissues, but high in GC tissues (P< 0.05). Also, they were weak in well-differentiated GC, but strong in poorly differentiated GC (P< 0.05). In addition, there was a significant correlation between Nrf2, HO-1, and VEGF (P< 0.05).Conclusion: The Nrf2/HO-1 axis may regulate the angiogenesis of GC via targeting VEGF. These findings provide a promising biomarker and potential treatment target for GC.Keywords: gastric cancer, angiogenesis, Nrf2, HO-1, VEGF

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