First KEGG and GO annotation were conducted for
First, KEGG and GO annotation were conducted for these 1251 genes. Then, combining the pathway enrichment analysis, we explored how these genes could function in breast cancer. We discovered that neuroactive ligand-receptor interaction was the most enriched pathway, which comprised numerous G protein-coupled receptors. Having been activated by their respective ligands, these receptors could control neuronal signaling and thus affect the behavior of animals , which was consistent with the results of the GO annotation that we conducted. In the TCGA dataset, analysis of pan-cancer showed that neuroactive ligand-receptor interaction ranked fifth among the most mutated pathways of malignancies . For patients with glioma, this pathway was a significant one and related to undesirable prognosis . The neuroactive ligand-receptor interaction pathway also played a vital role in breast cancer. For example, CNR1, as the core gene in this pathway, could encode G protein-coupled cannabinoid receptor, the activation of which was essential for cannabinoids to perform antiemetic function in patients undergoing chemotherapy for cancer . The low expression of this gene was associated with chemosensitivity . After the breast cancer LGX818 were treated with telocinobufagin, relevant genes, including chemosensitivity-related CNR1, were remarkably enriched in this pathway, which suggested that telocinobufagin was likely to regulate this pathway to improve the clinical outcome of patients suffering from breast cancer.
As a compound, telocinobufagin, has been discovered to play the role of immune activation or inhibitor . After breast cancer cells were treated with telocinobufagin, we found that 14 genes were enriched in the intestinal immune network for IgA production pathway. It was reported that this pathway was linked with inflammation and immunity, and it was also related with the onset and development of pancreatic cancer . Therefore, it could be inferred that telocinobufagin might regulate the immune and inflammation responses to influence breast cancer cells.
Considering the role of telocinobufagin in breast cancer, we focused on the interaction between these differentially expressed genes and proteins, and then constructed a PPI. We confirmed that the most interactive proteins included INSR, FGA, FGFR2, EPHA3, EFNA5, IGF1, KL, and KSR1, among which IGF1, KL, and KSR1 were found to function in the onset and development of breast cancer. The functions of the remaining genes were also reported in several studies, one of which demonstrated that the expression level of INSR was a key factor in influencing the treatment and survival of patients with breast cancer. The lowly expressed INSR, positive ER, and normal BMI would promise less clinical treatment but satisfactory outcome for patients suffering breast cancer . Moreover, FGFR2 was found to play an essential part in breast cancer. The suppression of FGFR2 signaling could revert the estrogen-independent phenotype that was promoted by the binding of transcription factors NFIB and YBX1 to the estrogen receptor . Inhibiting FGFR2 signaling remained a common targeted therapy for breast cancer in clinical research, which brought benefits to patients to a certain extent [, , ]. Based on previous studies, we inferred that telocinobufagin would change the gene expression profiles and regulate the key proteins to exert its influences. However, the specific mechanism of telocinobufagin requires further investigation.
Conflict of interest
Acknowledgements The current paper was supported by the Medical Excellence Award Funded by the Creative Research Development Grant from the First Affiliated Hospital of Guangxi Medical University.
Oxysterols are oxygenated derivatives of cholesterol produced by the oxidation by the CYP family of enzymes in the cells and falls in the bile acid synthesis or steroid synthesis pathway. Few oxysterols such as 7-hydroxy and 7-keto are also known to be produced in vivo by non-enzymatic radical oxidation mechanism. Although found in very low concentrations in most mammalian tissues, oxysterols play a crucial role in cholesterol and fatty acid metabolism, regulation of immune response and are also believed to be mediators in neurodegenerative disorders.