Role of tissue‐specific steroid metabolism in oral disease: Is there any clinical implication?

Abstract

The discovery of an oral glucocorticoid system has provided novel conceptual frameworks for understanding the effects of endogenous and exogenous corticosteroids in the oral cavity. For example, liquorice derivatives have long been used in the treatment of oral inflammatory conditions and it is now known that a chief constituent of liquorice root, glycyrrhetinic acid, inhibits 11β-hydroxysteroid dehydrogenase (11β-HSD) type 2 thus increasing local cortisol levels. Hence, targeting the local interconversion between inactive cortisone and active cortisol by 11β-HSD inhibitors/activators offers potentially advantageous strategies for the treatment of oral inflammatory and autoimmune conditions. The recent characterisation of a cancer-associated glucocorticoid system has further extended the implications of cortisol metabolism in oral disease. New evidence now questions the use of synthetic corticosteroids in patients with cancer and, possibly, in oral potentially malignant disorders. For example, cortisol production by cancer cells has been shown to inhibit tumour-specific CD8 T cells, to promote migration and invasion and to induce chemoresistance in vitro. This viewpoint briefly summarises the recent evidence for a role of the local steroid metabolism in oral oncology and immunology and its potential clinical implications.

Identification of Prognosis-related Hub RNA Binding Proteins Function through Regulating Metabolic Processes in Tongue Cancer

“…AMPK, HIF-1 signaling pathways and Glucose metabolism are widely recognized and heavily pursued for treatment of metabolic diseases, such as a variety of cancers [34][35][36][37]. Previous reports have demonstrated that the increased hormones occurred as cause of tongue cancer progression and revealed the components of the steroid biosynthetic pathways can be considered to be cancer biomarkers [38][39][40][41]. Thus, the enrichment of LEPR, PFKM, PGK1, and CYP19A1 in the aforementioned pathways suggests these prhRBPs as potential therapeutic targets.…”

Expression Profiles of GILZ and SGK-1 in Potentially Malignant and Malignant Human Oral Lesions

“…Tissue cortisol level is regulated by 11-β-hydroxysteroid dehydrogenases (11-β-HSDs) 1 and 2; 11-β-HSD1 metabolizes cortisone (inactive) to cortisol, which can be converted back to cortisone by 11-β-HSD2. Figure 1 summarizes some of the reported features of the glucocorticoid system in oral tissues [ 10 , 11 ]. Indeed, the demonstration of a reduction in 11-β-HSD2 expression in oral squamous cell carcinoma (SCC) has focused attention on the role of local generation of glucocorticoids in oral tissue pathologies [ 10 , 11 ].…”

“…Figure 1 summarizes some of the reported features of the glucocorticoid system in oral tissues [ 10 , 11 ]. Indeed, the demonstration of a reduction in 11-β-HSD2 expression in oral squamous cell carcinoma (SCC) has focused attention on the role of local generation of glucocorticoids in oral tissue pathologies [ 10 , 11 ].…”

“…The reduced expression of 11-β-HSD2 in oral SCC likely raises tissue cortisol level, resulting in glucocorticoid receptor-mediated effects. Consequently, it is proposed that the upregulation of pro-survival pathways coupled with impaired immune surveillance results in increased tumor size, reduced susceptibility to cytotoxic agents, and increased propensity for metastasis [ 10 , 11 ]. Importantly, GCs are potent inducers of glucocorticoid-induced leucine zipper (GILZ) and serum-glucocorticoid-regulated kinase-1 (SGK-1) expressions, which are implicated in the pathogenesis of various tumors as described in the text; however, their status in potentially malignant or malignant oral lesions is not known and is the subject of this study.…”

“…The focus of this study is to establish the expression profiles of GILZ and SGK-1 and its phosphorylated, active, form (pSGK-1) in oral tissue specimens of human subjects, clinically found as leukoplakia, ulcerative or mass-type lesions, and diagnosed microscopically as epithelial dysplasia or squamous cell carcinoma. Aside from relevance to exogenous glucocorticoid therapy or the generation of glucocorticoids by adrenal glands, this investigation takes added importance given the demonstration that oral mucosa possesses the metabolic machinery to generate cortisol [ 10 , 11 ] ( Figure 1 ). Accordingly, GILZ, SGK-1, and pSGK-1 immunoprofiles and semi-quantitative assessment of staining in dysplastic and malignant lesions were contrasted with those assessed in benign keratosis specimens as controls.…”