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

Yunning Huang; Yuanyuan Yang; Yuanyi Xu; Qian Ma; Fengying Guo; Yuan Zhao; Yuejia Tao; Mengqi Li; Jiaxin Guo

doi:10.2147/CMAR.S292461

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

Cancer Manag Res. 2021 Apr 12:13:3155-3169. doi: 10.2147/CMAR.S292461. eCollection 2021.

Authors

Yunning Huang^#¹, Yuanyuan Yang^#², Yuanyi Xu^#², Qian Ma^#^{3

4}, Fengying Guo², Yuan Zhao², Yuejia Tao², Mengqi Li², Jiaxin Guo²

Affiliations

¹ Department of Gastrointestinal Surgery, The Affiliated People's Hospital of Ningxia Medical University, Yinchuan City, Ningxia Province, 750001, People's Republic of China.
² Department of Pathology, Ningxia Medical University, Yinchuan City, Ningxia Province, 750004, People's Republic of China.
³ College of Life Sciences, Ningxia University, Yinchuan City, Ningxia Province, 750021, People's Republic of China.
⁴ College of Basic Medicine, Ningxia Medical University, Yinchuan City, Ningxia Province, 750004, People's Republic of China.

^# Contributed equally.

Abstract

Purpose: 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: HO-1; Nrf2; VEGF; angiogenesis; gastric cancer.

Grants and funding

This research was supported by Key Research and Development Project of Ningxia Province (grant nos. 2018BEG03010 and 2019BEG03007) and Natural Science Foundation Project of Ningxia Province (grant nos. 2020AAC03184).