Research Paper Volume 14, Issue 7 pp 3293—3312

Abnormal phenotype of Nrf2 is associated with poor prognosis through hypoxic/VEGF-A-Rap1b/VEGFR2 pathway in gastric cancer

Ya Yang1, , Xin Wang1, , Jia Zhang2, , Hao Gu1, , Song Zhang1, , Hao Sun1, , Junqi Liu1, , Ruitai Fan1, ,

  • 1 Department of Radiotherapy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan, China
  • 2 Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi, China

Received: November 11, 2020       Accepted: November 11, 2021       Published: April 13, 2022
How to Cite

Copyright: © 2022 Yang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Metastasis is the major cause of death in gastric cancer patients and altered expression of Nrf2 is associated with cancer development. This study assessed Nrf2 and HO-1 expression and hypoxia-induced Nrf2 expression in the promotion of metastatic potential of gastric cancer cells, the relationship of Rap1b and Nrf2 was also discussed. Nrf2 and HO-1 expression were significantly associated with clinicopathological characteristic and were independent prognostic predictors in gastric cancer patients. Hypoxia up-regulated the expression of Nrf2, HO-1 and HIF-1α, whereas knockdown of Nrf2 inhibited cell invasion capacity and reduced the expression of Nrf2, HO-1 and HIF-1α. Patients in the Rap1b (+) Nrf2 (+) group had worst overall survival compared with those from other groups. Knockdown of Rap1b and Nrf2 significantly inhibited cell invasion capacity in the common group compared with the other groups. Hypoxia or VEGF-A facilitated the nuclear translocation of Nrf2 through Rap1b or VEGFR2. Hypoxia or VEGF-A did not induce the phosphorylation of P-Erk1/2 and P-Akt after knockdown of Rap1b or VEGFR2. Hypoxia promoted the gastric cancer malignant behavior through the upregulation of Rap1b and Nrf2. Hypoxia/VEGF-A-Rap1b/VEGFR2 facilitated the nuclear translocation of Nrf2. Targeting Rap1b and Nrf2 may be a novel therapeutic strategy for gastric cancer.


CoCl2: Cobalt dichloride; CIH: chronic intermittent hypoxia; DMEM: Dulbecco’s Modified Eagle’s Medium; DAB: diaminobenzidine; FBS: Fetal bovine serum; ECL: enhanced chemiluminescence; GRIM-19: gene associated with retinoid-IFN-induced mortality 19; GAPDH: glyceraldehydes-3-phosphate dehydrogenase; HIF-1α: hypoxia -inducible factor-1 alpha; HO-1: heme oxygenase-1; Keap1: Kelch-like ECH-associated protein 1; MMP2: matrix metallopeptidase 2; OSCC: oral squamous cell carcinoma; OGD/R: oxygen-glucose deprivation/reoxygenation; OSC: Oxysophocarpine; PVDF: polyvinylidene fluoride; TME: tumor microenvironment; siRNA: small interfering RNA; VEGFR2: vascular endothelial growth factor receptor; TTB: 2,7,2’-trihydroxy-4,4’7’-trimethoxy-1,1’-Biphenanthrene.