An Integrated Pan-Cancer Analysis and Structure-Based Virtual Screening of GPR15

Abstract

G protein-coupled receptor 15 (GPR15, also known as BOB) is an extensively studied orphan G protein-coupled receptors (GPCRs) involving human immunodeficiency virus (HIV) infection, colonic inflammation, and smoking-related diseases. Recently, GPR15 was deorphanized and its corresponding natural ligand demonstrated an ability to inhibit cancer cell growth. However, no study reported the potential role of GPR15 in a pan-cancer manner. Using large-scale publicly available data from the Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) databases, we found that GPR15 expression is significantly lower in colon adenocarcinoma (COAD) and rectal adenocarcinoma (READ) than in normal tissues. Among 33 cancer types, GPR15 expression was significantly positively correlated with the prognoses of COAD, neck squamous carcinoma (HNSC), and lung adenocarcinoma (LUAD) and significantly negatively correlated with stomach adenocarcinoma (STAD). This study also revealed that commonly upregulated gene sets in the high GPR15 expression group (stratified via median) of COAD, HNSC, LUAD, and STAD are enriched in immune systems, indicating that GPR15 might be considered as a potential target for cancer immunotherapy. Furthermore, we modelled the 3D structure of GPR15 and conducted structure-based virtual screening. The top eight hit compounds were screened and then subjected to molecular dynamics (MD) simulation for stability analysis. Our study provides novel insights into the role of GPR15 in a pan-cancer manner and discovered a potential hit compound for GPR15 antagonists.

Identification of a 5-Gene-Based Scoring System by WGCNA and LASSO to Predict Prognosis for Rectal Cancer Patients

“…GPR15 expression was significantly positively correlated with the prognosis of patients with COAD (that is, the high expression had a longer OS) [ 30 ], which was also observed in our study of READ. Wang and Wang believed that GPR15 may be a tumor suppressor by regulating a serial of genes enriched in immune systems and increasing the infiltration of B cells (in neck squamous carcinoma, lung adenocarcinoma, and stomach adenocarcinoma), CD4+ T cells, and DCs (in neck squamous carcinoma and stomach adenocarcinoma) [ 30 ]. Similarly, we found that the expression of GPR15 was positively associated with the levels of tumor-infiltrating immune B cells and DCs and predicted that GPR15 could interact with DC-related CXCL12 to participate in RC progression.…”

“…Consistent with these findings, we also found that the expression of TCL1A was significantly positively correlated with the infiltration of DCs. Using TCGA and the genotype-tissue expression data, Wang and Wang found that GPR15 was significantly lowly expressed in COAD and READ compared with normal tissues [ 30 ], which was validated in our study. GPR15 expression was significantly positively correlated with the prognosis of patients with COAD (that is, the high expression had a longer OS) [ 30 ], which was also observed in our study of READ.…”

“…Using TCGA and the genotype-tissue expression data, Wang and Wang found that GPR15 was significantly lowly expressed in COAD and READ compared with normal tissues [ 30 ], which was validated in our study. GPR15 expression was significantly positively correlated with the prognosis of patients with COAD (that is, the high expression had a longer OS) [ 30 ], which was also observed in our study of READ. Wang and Wang believed that GPR15 may be a tumor suppressor by regulating a serial of genes enriched in immune systems and increasing the infiltration of B cells (in neck squamous carcinoma, lung adenocarcinoma, and stomach adenocarcinoma), CD4+ T cells, and DCs (in neck squamous carcinoma and stomach adenocarcinoma) [ 30 ].…”

The Role of GPR15 Function in Blood and Vasculature

“…Additional potential antagonists for GPR15 were identified using the in silico utilizing virtual screening technique [ 45 ]. At least eight compounds from a chemical database of 62,500 small molecules were identified that putatively antagonize GPR15.…”

Aberrant expression of WDR4 affects the clinical significance of cancer immunity in pan-cancer

“…Malignant tumours are one of the principal causes of mortality in both developing and developed nations, with limited therapeutic success achieved worldwide [ 1 , 2 ]. Currently, pan-cancer investigations have been generally utilized to explore the common features or heterogeneities involved in the existence and development of cancer [ 3 – 5 ]. Pan-cancer analysis reveals the similarities and differences between the genomes and cell changes of numerous carcinoma types that can distinguish several mutual characteristics or heterogeneities in crucial biological processes [ 3 ].…”