Investigating the Role of pH-sensing G Protein-Coupled Receptors GPR4 and GPR132 in Colorectal Cancer: Multi-Statistical, Survival, and Structural Analysis Approach

Abstract

Colorectal adenocarcinoma (COAD) is one of the leading causes of cancer-related mortality worldwide. Understanding the molecular mechanisms that contribute to cancer progression is a critical step for identifying therapeutic targets to combat COAD. GPR4 and GPR132, which are pH sensing G protein-coupled receptors (GPCRs), have recently emerged as a point of interest and linked to tumor progression, tumor microenvironment, and molecular signaling pathways. However, despite this, the roles these GPCRs play are still not fully understood. This study investigates the clinical and structural relevance of GPR4 and GPR132 in COAD through gene expression, survival, and structural analyses. Gene expression and clinical data were collected from The Cancer Genome Atlas (TCGA) and analyzed using various statistical and survival methods. Statistical tests and survival models revealed an increase in GPR4 expression and that higher stages were significantly associated with worsening patient survival outcomes, which suggests GPR4 to be a potential biomarker and therapeutic target. In contrast GPR132 showed a limited amount of clinical significance and was hindered by a lack of comprehensive clinical data. Additionally, AlphaFold and APBS were used to model wildtype and mutation GPR4 structures and electrostatic potential (ESP) maps across different pH levels. While electrostatic differences were inconclusive and need further in-depth investigation, structural comparisons discovered notable spatial changes between the transmembrane domain that contains position 115 and two other transmembrane domains. Overall, this study highlights prognostic potential in COAD and provides preliminary insights into how mutations may influence its structure and function.