The emerging double-edged sword role of Sirtuins in the gastric inflammation-carcinoma sequence revealed by bulk and single-cell transcriptomes

Histone modification and the inflammation-carcinoma sequence (ICS) have been acknowledgedly implicated in gastric carcinogenesis. However, the extremum expression of some histone modification genes (HMGs) in intestinal metaplasia (IM) rather than GC obscures the roles of HMGs in ICS. In this study, we assumed an explanation that the roles of HMGs in ICS were stage specific. Bulk RNA-seq on endoscopy biopsy samples from a total of 50 patients was accompanied by reanalysis of a set of published single-cell transcriptomes, which cross-sectionally profiled the transcriptomic features of chronic superficial gastritis (SG), atrophy gastritis (AG), IM, and early gastric cancer (GC). Differential analysis observed significantly peaked expression of SIRT6 and SIRT7 at IM. Weighted correlation network analysis on bulk transcriptome recognized significant correlations between SIRT1/6 and IM. The single-cell atlas identified one subgroup of B cells expressing high level of TFF1 (TFF1 (hi) naive B cell) that theoretically played important roles in defending microbial infection, while SIRT6 displayed a positive correlation with TFF1 (low) naive B cells. Moreover, gene set enrichment analysis at different lesions (SG-AG, AG-IM, and IM-GC) highlighted that gene sets contributing to IM, e.g., Brush Border, were largely enriched from co-expressing genes of Sirtuins (SIRTs) in AG-IM. Surveys of the genes negatively correlated with SIRT6 in public databases considered SIRT6 as tumor suppressors, which was confirmed by the cell proliferation and migration assays after transient transfection of SIRT6 overexpression vector into AGS cells. All the above observations were then confirmed by serial section-based immunohistochemistry against Ki-67, MUC2, MUC5AC, p53, and SIRT6 on the endoscopic submucosal dissection tissue. By contrast, the expression of the other HMGs varied even opposite within same family. Taken together, this study preliminarily demonstrated the two-edged sword role of SIRTs in ICS and, by extension, showed that the roles of HMGs in ICS were probably stage specific. Our study may provide new insights into and attract attention on gastric prevention and therapy targeting HMGs.