GPR68 limits the severity of chemical-induced oral epithelial dysplasia

Abstract

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.

Recent advances in acid sensing by G protein coupled receptors

“…[ 6 , 54 , 98 ]). As before, results do not seem to show any clear patterns: OGR1 was found to be involved in processes that promote or interfere with cancer progression [ 6 , 14 , 17 , 30 , 54 , 63 , 77 , 78 ]. Discrepancies may arise because some studies address a role for OGR1 in the host (tissue) whilst others look at OGR1 roles in cells making up the tumour tissue.…”

“…Research published in the past few years adds to the complicated picture. Several studies have investigated OGR1 in cancer, specifically in pancreatic, breast, ovarian, skin, liver, head and neck, colorectal and oesophageal cancer [ 5 , 6 , 14 , 18 , 30 , 33 , 48 , 54 , 63 , 77 , 78 , 88 , 96 , 98 , 101 ], ranging from pure expression (e.g. [ 5 , 48 ]) to functional studies in cells (e.g.…”

Molecular basis of proton-sensing by G protein-coupled receptors

“…These receptors are expressed in diverse cells that regulate central pH homeostasis 8 , pH sensing in the immune system [9][10][11] , and vascular responses to pH 12 . Understanding and precisely manipulating the function of these proton sensing GPCRs holds promise for a range of diseases like inflammatory bowel disease 10,13 , osteoarthritis 14 , and certain cancers [15][16][17] . Given the relevance of proton sensing GPCRs to pH-dependent physiology, it is important to understand how these receptors work at the molecular level.…”