NECTIN4 (PVRL4) expression in pancreatic cancer patients might be associated with a more unfavorable prognosis, independent of age at diagnosis, sex, and stage: A public microarray and RNA sequencing data based bioinformatics analysis.

Pancreatic cancer (PC) is known to be a highly fatal malignancy, and elucidating new molecular mechanisms is of great importance. In this study, we investigated NECTIN4 (PVRL4), which is associated with poor prognosis, via bioinformatics approach. We used following tools and datasets: For differential gene expression analysis, TCGA TARGET GTEx study on UCSC Xena, GSE183795, GSE71729 and GSE196009 GEO datasets; for associations with clinicopathological and promoter methylation features, UALCAN; for correlations with overall survival (OS), disease-free survival (DFS) gene chip database, and for correlations with OS and relapse-free survival (RFS) RNAseq database in the Kaplan-Meier (KM) plotter; for correlations with OS and Progression-Free Interval (PFI), DoSurvive; for immune infiltration correlations, TIMER3; for expression changes in hotspot mutations, GEPIA 3; for potentially related pathways, diseases, and processes, the Gscore online tool; for gene alterations detections, cBioPortal; and identifying potential targeting miRNAs, miRDB, TargetScanHuman 8.0, ENCORI, and DoSurvive. NECTIN4 (PVRL4) is upregulated in primary pancreatic adenocarcinoma in TCGA TARGET GTEx study (log2FC=2.015633, adj.P.Val=4.62E-21) and in pancreatic ductal adenocarcinomas in GSE183795 (log2FC=0.726, adj.P.Val=10-16.895) GSE196009 (log2FC=2.807, adj.P.Val=10-3.855) GSE71729 (log2FC= 1.227, adj.P.Val=10-10.318) datasets, and may be associated with unfavorable OS (p = 3.63E-02) and PFI (p = 8.09E-03) independent of age at diagnosis, sex, and stage in DoSurvive. In KM plotter RNA seq database, increased NECTIN4 (PVRL4) expression was statistically significantly associated only with shortened OS (p = 0.008). NECTIN4 (PVRL4) expressions are higher in the following traits than in others: In Asians compared to normals (p = 4.949700E-02) and Caucasian (p = 4.480000E-03); in chronic pancreatitis patients from normals (p=3.456300E-02); in grade 2 (p = 2.420600E-04) and grade 3 (p = 1.875500E-03) from grade 1; in TP53 mutants from nonmutants (p = 7.6379999999987E-05). NECTIN4 (PVRL4) correlates positively or negatively with many immune cell types, some of which are also associated with OS. NECTIN4 is upregulated in KRAS (log2FC=1.78, p = 1.05E-17), TP53 (log2FC=0.959, p = 1.22E-05), SMAD4 (log2FC=1.02, p = 0.000111), CDKN2A (log2FC=0.668, p = 0.0144), and RNF43 (log2FC=0.917, p = 0.0393) mutant samples. NECTIN4 (PVRL4) is associated with many pathways, processes, and diseases these may be related to PC. Six patients have amplification, and one patient has a splice mutation. hsa-miR-329-3p and hsa-miR-5586-5p may be potential negative regulatory miRNAs of NECTIN4 (PVRL4). NECTIN4 (PVRL4) may be associated with many pathways awaiting experimental illumination in PC.