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Published on: March 16, 2020
An Integrated Pan-Cancer Analysis and Structure-Based Virtual Screening of GPR15
Yanjing Wang1, Xiangeng Wang1, Yi Xiong1
1State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, and Joint Laboratory of International Cooperation in Metabolic and Developmental Sciences, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200240, China.
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.
Insights
G protein-coupled receptor 15 (GPR15) expression impacts cancer prognosis across multiple types. Lower GPR15 levels are seen in colorectal cancers, while higher levels correlate with better outcomes in others, suggesting GPR15 as a potential immunotherapy target.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- G protein-coupled receptor 15 (GPR15) is linked to HIV, inflammation, and smoking-related diseases.
- GPR15, also known as BOB, is an orphan G protein-coupled receptor (GPCR).
- Recent studies deorphanized GPR15, revealing its ligand inhibits cancer cell growth, but its pan-cancer role remains unexplored.
Purpose of the Study:
- To investigate the pan-cancer role of GPR15 expression.
- To analyze the correlation between GPR15 expression and patient prognosis across various cancer types.
- To identify potential therapeutic strategies targeting GPR15.
Main Methods:
- Utilized large-scale data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases.
- Analyzed GPR15 expression levels in normal versus tumor tissues.
- Performed correlation analyses between GPR15 expression and prognosis in 33 cancer types.
- Conducted 3D structure modeling and structure-based virtual screening of GPR15, followed by molecular dynamics simulations.
Main Results:
- GPR15 expression was significantly lower in colon adenocarcinoma (COAD) and rectal adenocarcinoma (READ) compared to normal tissues.
- GPR15 expression positively correlated with prognosis in COAD, head and neck squamous cell carcinoma (HNSC), and lung adenocarcinoma (LUAD).
- GPR15 expression negatively correlated with prognosis in stomach adenocarcinoma (STAD).
- Gene sets upregulated in high GPR15 expression groups were enriched in immune system pathways.
- Identified eight potential hit compounds for GPR15 antagonists via virtual screening and MD simulations.
Conclusions:
- GPR15 plays a significant role in various cancers, influencing prognosis and potentially serving as an immunotherapy target.
- The study identified potential GPR15 antagonist compounds, offering novel therapeutic avenues.
- GPR15's involvement in immune system modulation warrants further investigation in cancer immunotherapy.
