DPP9: Comprehensive In Silico Analyses of Loss of Function Gene Variants and Associated Gene Expression Signatures in Human Hepatocellular Carcinoma.

Jiali Carrie Huang,Mark D. Gorrell,Abdullah Al Emran,Hui Emma Zhang,Justine Moreno Endaya,Geoffrey W. McCaughan

doi:10.3390/cancers13071637

Jiali Carrie Huang, Mark D. Gorrell + Show 4 more

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https://doi.org/10.3390/cancers13071637

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Abstract

Simple SummaryThis in silico study aimed to investigate associations between dipeptidyl peptidase (DPP) 9 mRNA expression, survival and gene signature in human hepatocellular carcinoma (HCC). DPP9 loss-of-function exonic variants were mostly associated with cancers. In HCC patients, DPP9 and the closely related genes DPP4 and DPP8 were upregulated in liver tumors. High co-expression of genes that were positively correlated with DPP4, DPP8 and DPP9 was associated with poor survival in HCC patients. These findings strongly implicate the DPP4 gene family, especially DPP9, in the pathogenesis of human HCC and therefore encourages future functional studies.Dipeptidyl peptidase (DPP) 9, DPP8, DPP4 and fibroblast activation protein (FAP) are the four enzymatically active members of the S9b protease family. Associations of DPP9 with human liver cancer, exonic single nucleotide polymorphisms (SNPs) in DPP9 and loss of function (LoF) variants have not been explored. Human genomic databases, including The Cancer Genome Atlas (TCGA), were interrogated to identify DPP9 LoF variants and associated cancers. Survival and gene signature analyses were performed on hepatocellular carcinoma (HCC) data. We found that DPP9 and DPP8 are intolerant to LoF variants. DPP9 exonic LoF variants were most often associated with uterine carcinoma and lung carcinoma. All four DPP4-like genes were overexpressed in liver tumors and their joint high expression was associated with poor survival in HCC. Increased DPP9 expression was associated with obesity in HCC patients. High expression of genes that positively correlated with overexpression of DPP4, DPP8, and DPP9 were associated with very poor survival in HCC. Enriched pathways analysis of these positively correlated genes featured Toll-like receptor and SUMOylation pathways. This comprehensive data mining suggests that DPP9 is important for survival and that the DPP4 protease family, particularly DPP9, is important in the pathogenesis of human HCC.

Highlights

Dipeptidyl peptidase (DPP) 9, DPP4, DPP8 and fibroblast activation protein (FAP) are the enzymatic members of the DPP4 family of serine proteases and have been implicated in cancer pathogenesis [1]
The top ranking TP53 regulation pathway in our analyses indicates that DPP8 and DPP9 overexpression could be oncogenic in human hepatocellular carcinoma (HCC)
This study reports the first comprehensive data mining of associations between DPP9 expression, survival and gene expression signatures in human HCC

Summary

Introduction

Dipeptidyl peptidase (DPP) 9, DPP4, DPP8 and fibroblast activation protein (FAP) are the enzymatic members of the DPP4 family of serine proteases and have been implicated in cancer pathogenesis [1]. DPP9 is ubiquitously expressed in tissues [2] and has diverse roles in cell behaviors [3], immune regulation [4,5,6] and cancer [7,8,9]. Overexpression of DPP9 in NSCLC is independently associated with poor 5-year overall survival [7]. In colorectal cancer, greater DPP9 expression is associated with poor prognosis [8]. In patients with oral squamous cell carcinoma, lower DPP9 expression correlates with poor survival [9]. These data suggest that DPP9 has different roles in various types of cancers

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