Associations between DPP9 expression, survival and gene expression signature in human hepatocellular carcinoma: Comprehensive in silico analyses

Abstract

Background Dipeptidyl peptidase (DPP) 9, DPP8, DPP4and fibroblast activation protein (FAP) are the four enzymatically active members of the S9b protease family1,21. Associations of DPP9 or DPP8 with human liver cancer have not been examined. Genome-wide association studies have found that intronic single nucleotide polymorphisms (SNPs) in DPP9 are associated with severe COVID-19 and lung fibrosis3. However, exonic SNPs in DPP9 and DPP9 loss of function (LoF) variants have not been explored. Methods Large-scale human genetic databases including The Cancer Genome Atlas (TCGA) were interrogated. Results We found that DPP8 and DPP9 are intolerant to LoF variants, which strongly suggests that these enzymes, but not DPP4 and FAP, are essential for life in humans. Uterine corpus endometrial carcinoma (UCEC) was the most commonly diagnosed cancer in patients with DPP9 LoF variants, and low DPP9 expression was associated with poor survival in UCEC. The two DPP9 intronic SNPs that have been associated with lung fibrosis and COVID-19 were not associated with liver fibrosis or cancer. All four enzymes were overexpressed in liver tumours. Increased DPP9 expression was associated with obesity in HCC patients, but there was no association between DPP9 expression intensity and HCC survival. However, high expression of all four DPP4-like genes was significantly associated with poor survival in HCC. Moreover, high expression of genes that positively correlated with overexpression of DPP4, DPP8, and DPP9 was associated with very poor survival in HCC (Fig. 1). Enriched pathways analysis of these in-common correlated genes featured Toll-like receptor (TLR) and SUMOylation pathways. Conclusion This comprehensive data mining suggests that DPP9 is essential for human survival and the DPP4 protease family is important in cancer pathogenesis.