Abstract
BackgroundGastric cancer (GC) is a common malignancy of the digestive system. Antioxidant activity is regarded as a possible mechanism in ectopic cancer. Hence, oxidative stress regulation is being evaluated for cancer treatment. Previous research has demonstrated that Nestin is associated with antioxidative resistance via its modulation of the Kelch-like ECH-associated protein 1 (Keap1)–nuclear factor erythroid 2-related factor 2 (Nrf2) pathway.MethodsWe determined the role of Nestin-mediated redox homeostasis and tumor phenotypes in GC cells.ResultsWe found that the Nestin expression level was high in GC tissues and cell lines. Nestin knockdown in the GC cell lines SGC-7901 and MKN-45 reduced viability, induced apoptosis, decreased antioxidant enzyme generation, and repressed GC metastasis. Nestin binds to Keap1, resulting in Nrf2 degradation and influencing downstream gene expression. Nestin knockdown resulted in the downregulation of Nrf2 expression in GC cells. The restoration of Nrf2 expression or treatment with the Nrf2 activator sulforaphane counteracted the inhibitory effect of Nestin knockdown on the proliferation, migration, invasion, and antioxidant enzyme production in GC cells. Moreover, xenograft GC tumors exhibited a slower growth rate than those of the control group in vivo.ConclusionsTaken together, these findings suggest that the Nestin–Keap1–Nrf2 axis confers oxidative stress resistance and plays an important role in the proliferation, migration, and invasion of GC cells.
Highlights
Gastric cancer (GC) is a common malignancy of the digestive system
The study findings indicated that the Nestin– Kelch-like ECH-associated protein 1 (Keap1)–nuclear factor erythroid 2-related factor 2 (Nrf2) pathway serves as a target for suppressing malignant GC phenotypes, including proliferation and metastasis
The mRNA and protein expression of Nestin was upregulated in GC cells compared with that in GES-1 cells, as assessed using Quantitative polymerase chain reaction (qPCR) and Western blot (WB) (Fig. 1B, C); these results suggest that nestin plays a role in GC development
Summary
Nestin expression in GC tissues and cells To determine the role of Nestin during GC development, we examined its expression using qPCR in 22 GC tissues and 9 healthy gastric tissues. We observed that the protein expression level of Nestin and Bach significantly decreased after Nestin knockdown (Fig. 4C–E) These data suggest that Nestin knockdown influences the migration and invasion of GC cells. Nrf overexpression and SF treatment counteracted the effect of Nestin knockdown on tumor phenotypes and the antioxidant capacity of GC cells Given the previous study results indicating that Nestin and Nrf play essential roles in tumor phenotype and cellular redox homeostasis of lung cancer, we hypothesized that Nrf is involved in the Nestinmodulated GC cell viability, apoptosis, antioxidant gene expression, and metastasis. To examine whether Nrf regulates Nestin knockdown-repressed GC cell metastasis, the wound healing assay and Transwell invasion assay were performed and the Bach expression level was determined using both qPCR and WB analysis. Tumor volume monitoring revealed that Nestin knockdown slowed the tumor growth rate
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