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

Abstract

Glucocorticoid-induced leucine zipper and serum-glucocorticoid-regulated kinase-1 (SGK-1) are major glucocorticoid-inducible proteins. Recent studies indicate the local production of cortisol in oral mucosa, which can impact the tissue generation of glucocorticoid-induced leucine zipper (GILZ) and SGK-1. Furthermore, GILZ and SGK-1 play pathogenic roles in a variety of cancers, but their status in potentially malignant (e.g., epithelial dysplasia) or malignant oral lesions remains unknown. This study tested the hypothesis that expression profiles of GILZ and SGK-1, along with the phosphorylated (active) form of SGK-1 (pSGK-1), are different in epithelial dysplasia than squamous cell carcinoma. Accordingly, archived paraffin-embedded biopsy samples were subjected to immunohistochemistry to establish tissue localization and the profile of proteins of interest, while hematoxylin-eosin stained tissues were used for histopathological assessment. Based on histopathological examinations, tissue specimens were categorized as displaying mild-moderate or severe epithelial dysplasia and squamous cell carcinoma; benign keratosis specimens served as controls. All the tissue specimens showed staining for SGK-1 and pSGK-1; however, while SGK-1 staining was primarily cytoplasmic, pSGK-1 was mainly confined to the cell membrane. On the other hand, all the tissue specimens displayed primarily nuclear staining for GILZ. A semi-quantitative analysis of immunohistochemistry staining indicates increased GILZ expression in epithelial dysplasia but reversal in squamous cell carcinoma to a level seen for benign keratosis. On the other hand, the SGK-1 and pSGK-1 expressions decreased for squamous cell carcinoma specimens compared with benign keratosis or dysplastic specimens. Collectively, in this cross-sectional study, immunostaining patterns for proteins of interest do not seemingly differentiate epithelial dysplasia from squamous cell carcinoma. However, subcellular localization and expression profiles for GILZ, SGK-1, and pSGK-1 are suggestive of differential functional roles in dysplastic or malignant oral lesions compared with benign keratosis.

Potential Causal Association between Depression and Oral Diseases: A Mendelian Randomization Study

“…A study has revealed that depression inhibits natural killer cells and DNA repair enzymes, which are essential for defense mechanisms against cancer [66]. Furthermore, cortisol secretion is increased in patients with depression, and local cortisol production in the oral mucosa upregulates serum glucocorticoid-regulated kinase-1 (SGK-1) expression [67,68]. SGK-1 activation and expression can favor the invasiveness and metastasis of human tumors, including tongue cancer [69].…”

Serum Glucocorticoid-Regulated Kinase-1 in Ischemia-Reperfusion Injury: Blessing or Curse

“…For example, following serum stimulation, SGK-1 enters the nucleus while it is found in the cytosol in response to glucocorticoids or hypertonic shock. It is also found in mitochondria likely regulating cellular energy metabolism and autophagy and is associated with plasma membrane in both non-malignant and malignant oral lesions (Cordas et al, 2007;O'Keeffe et al, 2013;Zhu et al, 2020;Zhou et al, 2019;Mozaffari and Abdelsayed, 2021). Collectively, these observations indicate the complex and multifaceted role of SGK-1 in physiological processes and pathological conditions.…”

Expression profiles of glucocorticoid-inducible proteins in human papilloma virus-related oropharyngeal squamous cell carcinoma

“…Aside from the use of glucocorticoids for a variety of noncancer disorders, they are also used for treatment of lymphohematopoietic neoplasms and as adjuvant therapy in non-hematological malignancies in order to limit adverse effects of chemotherapy and/or radiotherapy (7). Importantly, the following aspects are of relevance in relation to glucocorticoids and HPV-OPSCC.…”

“…This is consistent with intense interest in unraveling of the immune infiltrative landscape of HPV-positive vs. -negative head and neck tumors which, in turn, would help to better understand more favorable clinical outcome of HPVpositive than -negative squamous cell carcinoma and also strengthen the rationale for immunotherapy modalities (10-12). Third, glucocorticoids can affect the outcome of epithelial tumors via a number of mechanisms including impaired immune surveillance, anti-apoptotic effects, increased tumor cell energy metabolism and promoting chemotherapy resistance (7). Fourth, glucocorticoids regulate expression of several proteins which, aside from regulating immune and anti-inflammatory responses of glucocorticoids, they are implicated in etiopathogenesis of various cancers; these include the glucocorticoid-induced leucine zipper (GILZ), serum glucocorticoid-regulated kinase-1 (SGK-1) and Annexin-A1 (ANXA1) (13)(14)(15).…”

“…Fourth, glucocorticoids regulate expression of several proteins which, aside from regulating immune and anti-inflammatory responses of glucocorticoids, they are implicated in etiopathogenesis of various cancers; these include the glucocorticoid-induced leucine zipper (GILZ), serum glucocorticoid-regulated kinase-1 (SGK-1) and Annexin-A1 (ANXA1) (13)(14)(15). Indeed, we recently showed differential cellular localization of GILZ, SGK-1 and phosphorylated (active) form of SGK-1 (pSGK-1) in potentially malignant and malignant human oral lesions (i.e., HPV-negative) (7). However, the status of glucocorticoid-inducible proteins in HPV-OPSCC remain to be established.…”