GPR68 limits the severity of chemical-induced oral epithelial dysplasia

• Published in: Scientific reports Vol. 13; no. 1; pp. 353 - 11
• Main Authors: Shore, David, Griggs, Nosakhere, Graffeo, Vincent, Amin, A. R. M. Ruhul, Zha, Xiang-ming, Xu, Yan, McAleer, Jeremy P.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07-01-2023; Nature Publishing Group; Nature Portfolio
• Subjects: 4-Nitroquinoline-1-oxide - toxicity; 631/67/1536; 631/67/1665; Acidification; Acidity; Angiogenesis; Animals; Carcinogenesis - pathology; Carcinoma, Squamous Cell - pathology; Cell Transformation, Neoplastic; Drinking water; Dysplasia; Glycolysis; Head & neck cancer; Head and neck carcinoma; Head and Neck Neoplasms - chemically induced; Head and Neck Neoplasms - genetics; Humanities and Social Sciences; Hyperplasia; Immunoregulation; Lymphocytes T; Male; Malignancy; Mice; Microenvironments; multidisciplinary; Ovarian cancer; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Science; Science (multidisciplinary); Squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck; Tumor Microenvironment; Tumorigenesis
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-023-27546-y

Head and neck cancer is the sixth most common malignancy, and there is an urgent need to identify physiological processes contributing to tumorigenesis. Extracellular acidification caused by aerobic glycolysis within tumor microenvironments can stimulate proton-sensing receptors. GPR68, or ovarian cancer G protein-coupled receptor 1, responds to extracellular acidity and is highly expressed in head and neck squamous cell carcinoma (HNSCC) as well as normal esophageal tissue. To study the role of GPR68 in oral dysplasia, wild-type and GPR68
−/−
mice were treated with 4-Nitroquinoline N-oxide (4NQO) in drinking water for 11–13 weeks, followed by normal water for 11–12 weeks. 4NQO treatment resulted in 45 percent of GPR68
−/−
mice developing severe dysplasia or squamous cell carcinoma compared to only 10.5 percent of GPR68
+/+
mice. This correlated with increased frequencies of regulatory T cells in the spleens of male GPR68
−/−
mice. Dysplastic regions of the tongue had increased CD31 staining compared to normal regions in both GPR68
−/−
and GPR68
+/+
mice, suggesting that angiogenesis was GPR68-independent. RNA knockdown studies using HNSCC cell lines demonstrated no direct effect of GPR68 on survival or growth. Overall, we demonstrate that GPR68-deficiency worsens the severity of chemical-induced oral dysplasia, suggesting a protective role for this gene in tumorigenesis.