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. 2023 Apr 13;160(1):15.
doi: 10.1186/s41065-023-00277-w.

γ-tocotrienol regulates gastric cancer by targeting notch signaling pathway

Ling Xie  1 , Juan Yan  2
Affiliations

γ-tocotrienol regulates gastric cancer by targeting notch signaling pathway

Ling Xie et al. Hereditas. .

Abstract

Background: Gastric cancer is a common cause of death from cancer and an important global health care issue. Consequently, there is an urgent need to find new drugs and therapeutic targets for the treatment of gastric cancer. Recent studies have shown that tocotrienols (T3) have significant anticancer ability in cancer cell lines. Our previous study found that γ-tocotrienol (γ-T3) induced apoptosis in gastric cancer cells. We further explored the possible mechanisms of γ-T3 therapy for gastric cancer.

Methods: In this study, we treated gastric cancer cells with γ-T3, collect and deposit the cells. γ-T3-treated gastric cancer cells group and untreated group were subjected to RNA-seq assay, and analysis of sequencing results.

Results: Consistent with our previous findings, the results suggest that γ-T3 can inhibit mitochondrial complexes and oxidative phosphorylation. Analysis reveals that γ-T3 has altered mRNA and ncRNA in gastric cancer cells. Significantly altered signaling pathways after γ-T3 treatment were enriched for human papillomavirus infection (HPV) pathway and notch signaling pathway. The same significantly down-regulated genes notch1 and notch2 were present in both pathways in γ-T3-treated gastric cancer cells compared to controls.

Conclusions: It is indicated that γ-T3 may cure gastric cancer by inhibiting the notch signaling pathway. To provide a new and powerful basis for the clinical treatment of gastric cancer.

Keywords: Gastric cancer; Mitochondria; Notch signaling pathway; Oxidative phosphorylation; γ-tocotrienol.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
RNA-seq assay of γ-T3-treated gastric cancer cells. MKN-45 cells were incubated for 24 h with γ-T3 (30umol/L). a Expression density plots of γ-T3-treated and control samples. b Expression distribution boxplot of γ-T3-treated and control samples. F: γ-T3-treated group; C: control group. n = 3
Fig. 2
Fig. 2
Changes in γ-T3-treated gastric cancer cells. a Principal component analysis of mRNA. b Principal component analysis of ncRNA. F: γ-T3-treated group; C: control group. n = 3
Fig. 3
Fig. 3
γ-T3 modifies the gene expression of mRNA and ncRNA in gastric cancer cells. a Differential expression analysis of mRNA and ncRNA genes. b, c Volcano and heat map analysis of mRNA in γ-T3-treated group and control group. d, e Volcano and heat map analysis of ncRNA in γ-T3-treated group and control group. Genes with |log2FoldChange|≥ log21.5 and padj < 0.05 as differentially expressed genes screening criteria. F_VS_C: γ-T3-treated group VS control group. F: γ-T3-treated group; C: control group. n = 3
Fig. 4
Fig. 4
γ-T3 influences the gene function of gastric cancer cell. a, b BP involved in the decreased mRNA expression of genes in the γ-T3-treated group compared to the control group. c, d CC involved in the decreased mRNA expression of genes in the γ-T3-treated group compared to the control group. e, f MF involved in the decreased mRNA expression of genes in the γ-T3-treated group compared to the control group. p < 0.05. n = 3
Fig. 5
Fig. 5
γ-T3 inhibits mitochondrial function and activates TNF signaling in gene function. a, b GSEA of γ-T3 in the BP of GO gene set. c, d GSEA of γ-T3 in the CC of GO gene set. e, f GSEA of γ-T3 in the MF of GO gene set. p < 0.05. n = 3
Fig. 6
Fig. 6
γ-T3 inhibits oxidative phosphorylation in gastric cancer cells. a, b GSEA of γ-T3 in the molecular function of KEGG gene set. p < 0.05. n = 3
Fig. 7
Fig. 7
γ-T3 down-regulates notch1 and notch2 expression levels. a, b The KEGG pathway involved in the mRNA of the genes downregulated in the γ-T3 treatment group compared to the control group. c Venn diagram of genes involved in the HPV pathway and the notch signaling pathway in the γ-T3-treated group down-regulated pathway compared to the control group. p < 0.05. n = 3
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