Vasoactive Intestinal Peptide (VIP) Regulates ZEB1 in Cancer Open Access

Rao, Ishani (Spring 2022)

Permanent URL: https://etd.library.emory.edu/concern/etds/pg15bg088?locale=en
Published

Abstract

In cancer immunology, VIP (vasoactive intestinal peptide) is a neuropeptide with pleiotropic effects including inhibiting T-cell activation, increasing regulatory T-cell frequency, and augmenting the immunosuppressive activity of myeloid-derived suppressor cells. VIP expression by cancer may represent a paracrine immune-check-point pathways as well as having autocrine effects on cancer growth. We used an in silico model to identify genes whose over-expression in cancer was correlated with elevated VIP expression and confirmed the role of VIP-receptor signaling in vitro using VIP-R antagonists. The TCGA PanCan dataset (analysis per UCSC Xena) was used to compare mRNA expression data of VIP versus 760 genes involved in 48 cancer-related pathways. A positive association was defined as Pearson’s Coefficient R-values >0.3. Expression of target genes and VIP were confirmed by Western blot analysis in cancer cell lines, and VIP-R signaling was inhibited using ANT008, a novel VIP-R inhibitor. A significant correlation (R>0.3) between VIP expression and 10 genes was observed (Table 1). Grouping cancers by germ-layer analysis demonstrated the strongest (R>0.4) associations in ectodermal and mesodermal-derived cancers. Histologically, the highest single association with VIP was with ZEB1 expression in stomach adenocarcinoma (R = 0.7643). In vitro experiments using Jurkat T-cells confirmed expression of VIP and ZEB1 protein. Treatment of Jurkat cells treated with the VIP antagonist ANT-08 (10 μM) demonstrated a reduction in ZEB1 total protein expression when VIP-R signaling was inhibited. The results demonstrate autocrine signaling between VIP expression and cancer-associated gene pathways. The ZEB1 transcription factor is a known EMT (epithelial-mesenchymal transition) regulator, and our in vitro studies demonstrate this pathway is therapeutically targetable using a VIP antagonist. 

Table of Contents

Introduction                                                                                                                                                                                       1-6

Methods                                                                                                                                                                                              6-8

Results                                                                                                                                                                                               8-16

Discussion                                                                                                                                                                                      16-20

References                                                                                                                                                                                      20-23

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