Research on the role of SOX9 in regulating metabolic reprogramming in diffuse large B cell lymphoma

Abstract

Objective·To explore the role played by the differentially expressed SRY-box transcription factor 9 (SOX9) gene in diffuse large B cell lymphoma (DLBCL), particularly in the regulation of metabolic reprogramming in the germinal center B-cell (GCB) like subtype.Methods·The clinical information and gene expression profile data of 481 DLBCL patients retrieved from the NCICCR-DLBCL database were included. Data analysis and visualisation were performed by using R language version 4.1.3. The classification was performed by using a cell of origin subtype (COO) classification algorithm based on RNA-seq sequencing of expression. ABC/GCB features were used to annotate gene sets, and the classification was verified by gene set enrichment analysis. The ABC and GCB subgroup was dichotomised based on the mean expression of SOX9. Differential analysis was performed by using the DEseq2 package. The relationship between SOX9 and ABC-DLBCL metabolism was analysed by using KEGG (Kyoto Encyclopedia of Genes and Genomes) with the Hallmark annotation set. The survival curves were plotted by using the Kaplan-Meier method. The pan-cancer analysis was performed by using GEPIA2. The microenvironmental scoring analysis was performed by the ESTIMATE package.Results·Of the 481 DLBCL patient samples, all the patients had RNA-seq expression data, 421 had clinical staging, 335 had international prognostic index (IPI) scores and 234 had survival data. The classification yielded 232 (48.2%) ABC subtypes, 173 (36.0%) GCB subtypes and 76 (15.8%) unclassified, consistent with the proportions declared in the database, and the enrichment analysis was verified to be consistent with the ABC/GCB expression profile. Compared to the high SOX9 expression group, the overall survival was shorter in the low SOX9 expression group and the prognostic score was worse. The pan-cancer analysis showed that this phenomenon was also seen in other tumor types. The differential analysis showed that there were 156 upregulated genes and 1 826 downregulated genes in the GCB subtype in the low SOX9 expression group, compared to the high SOX9 expression group. For metabolic processes, down-regulated genes were enriched in glycolysis.Conclusion·In the ABC subtype of DLBCL, the SOX9 gene affects the biological features of ABC-DLBCL by regulating metabolic reprogramming, and low expression of SOX9 in DLBCL, possibly caused by high methylation, predicts decreased glycolysis in tumors. The proportion of tumor stromal cells decreases, showing a worse prognosis.

Keywords

• sry-box transcription factor 9 (sox9)
• diffuse large b cell lymphoma (dlbcl)
• metabolic reprogramming