The oncogenic roles of GPR176 in ovarian cancer: a molecular target for aggressiveness and gene therapy

Introduction: G-protein-coupled receptor 176 (GPR176) is a member of the G-protein coupled receptor (GPCR) 1 family and produces a 515 amino acid glycosylated protein. Materials: and Methods: In the present study, GPR176 expression was detected using immunohistochemistry (IHC) and compared with clinicopathological characteristics of ovarian cancer using bioinformatics analysis. GPR176-related genes and pathways were analyzed using bioinformatics analysis. In addition, the effects of GPR176 on the phenotypes of ovarian cancer cells were investigated. Results: : GPR176 mRNA expression positively correlated with older age, clinicopathological staging, tumor residual status, and unfavorable survival of ovarian cancer (p < 0.05) but negatively with purity loss, infiltration of B cells, and CD8+ T cells (p < 0.05). Gene Set Enrichment Analysis (GSEA) showed that differential expression of the GPR176 gene was involved in focal adhesion, ECM-receptor interaction, ribosome, oxidative phosphorylation, actin skeleton, cytokine-cytokine receptor interaction, gap junction, and cell adhesion molecules (p < 0.05). STRING and Cytoscape were used to determine the top 10 nodes (FN1, COL1A1, MMP2, COL1A2, COL3A1, THBS1, ACAN, DCN, COL5A1, LUM) which were downregulated in ovarian cancer (p < 0.05). Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that GPR176-related genes were categorized into the AGE-RAGE signaling pathway in diabetic complication, ECM receptor interaction, protein digestion and absorption, ECM structural constituent and organization, and collagen trimer (p < 0.05). GPR176 overexpression promoted the proliferation, anti-apoptosis, anti-pyroptosis, migration and invasion of ovarian cancer cells with overexpression of N-cadherin, Zeb1, Snail, Twist1, and underexpression of gasdermin D, caspase 1, and E-cadherin. These results indicated that GPR176 might be involved in the progression of ovarian cancer by deteriorating aggressive phenotypes. Conclusion: GPR176 could potentially be used as a biomarker to indicate the aggressive behavior and poor prognosis of ovarian cancer and a target of genetic therapy.