Sphingosine kinase 1 facilitates gastric cancer progression via gene methylation-mediated mechanisms.

BACKGROUND

Gastric cancer (GC) stands as a prevalent gastrointestinal malignancy that poses a grave threat not only to human health and survival but also burdens public health systems. Recent studies have revealed a significant upregulation of sphingosine kinase 1 () expression in GC tissues, which is closely associated with the malignant progression of GC and adverse patient outcomes. However, the precise role of in GC progression remains unclear. Therefore, this study aimed to investigate whether promotes GC progression by modulating the DNA methylation of signal transducer and activator of transcription.

METHODS

The results of this study were primarily obtained via fluorescence quantitative polymerase chain reaction (PCR), immunoblotting, methylation-specific PCR, Cell Counting Kit-8 (CCK8) assay, Transwell assay, flow cytometry, hematoxylin-eosin staining, and immunohistochemistry. Differences in the expression of and in cancer and paracancerous tissues were detected. The regulatory role of on STAT1 was then determined via the overexpression and knockdown of and methyltransferase inhibitor. Finally, the regulatory ability of in organism was further verified by tumor load mouse experiments.

RESULTS

Through the Kaplan-Meier plotter online database, it was found that the expression of and STAT1 was significantly different in patients with GC. Using The Cancer Genome Atlas (TCGA) GC data (n=375), we identified a significant positive correlation between SPHK1 mRNA expression and STAT1 promoter methylation (Spearman's r=0.68, P<0.001). GEPIA survival analysis of 562 GC patients further showed that high SPHK1 expression was associated with shorter overall survival [hazard ratio (HR) =1.82, 95% confidence interval (CI): 1.23-2.71, P<0.001], consistent with our experimental findings. Testing of clinical samples verified the above results and found increased methylation of the gene. Knockdown of in cancer cells reduced gene methylation and inhibited cancer cell viability, while its overexpression increased gene methylation and enhanced cancer cell proliferation. The addition of methylase inhibitors effectively slowed down the methylation of the gene from , thereby inhibiting the proliferation of cancer cells. Finally, GC mouse model experiments showed that regulated the development of cancer through methylation of the gene.

CONCLUSIONS

This study clarified the mechanism by which affects the development of GC through regulating the methylation of the gene and provides a certain theoretical basis for the clinical exploration of novel methods for treating GC.