Gene Expression Analysis Links Autocrine Vasoactive Intestinal Peptide and ZEB1 in Gastrointestinal Cancers

VIP (vasoactive intestinal peptide) is a 28-amino acid peptide hormone expressed by cancer and the healthy nervous system, digestive tract, cardiovascular, and immune cell tissues. Many cancers express VIP and its surface receptors VPAC1 and VPAC2, but the role of autocrine VIP signaling in cancer as a targetable prognostic and predictive biomarker remains poorly understood. Therefore, we conducted an in silico gene expression analysis to study the mechanisms of autocrine VIP signaling in cancer. VIP expression from TCGA PANCAN tissue samples was analyzed against the expression levels of 760 cancer-associated genes. Of the 760 genes, 10 (MAPK3, ZEB1, TEK, NOS2, PTCH1 EIF4G1, GMPS, CDK2, RUVBL1, and TIMELESS) showed statistically meaningful associations with the VIP (Pearson's R-coefficient > |0.3|; p < 0.05) across all cancer histologies. The strongest association with the VIP was for the epithelial-mesenchymal transition regulator ZEB1 in gastrointestinal malignancies. Similar positive correlations between the VIP and ZEB1 expression were also observed in healthy gastrointestinal tissues. Gene set analysis indicates the VIP is involved in the EMT and cell cycle pathways, and a high VIP and ZEB1 expression is associated with higher median estimate and stromal scores These findings uncover novel mechanisms for VIP- signaling in cancer and specifically suggest a role for VIP as a biomarker of ZEB1-mediated EMT. Further studies are warranted to characterize the specific mechanism of this interaction.