Reciprocal Regulation of HSD11B1 and HSD11B2 Predicts Glucocorticoid Sensitivity in Childhood Acute Lymphoblastic Leukemia

Sai, Shuji; Esteves, Cristina L.; Kelly, Val; Sakaguchi, Kimiyoshi; McAndrew, Rachel; Chudleigh, Sandra; Spence, Alison; Gibson, Brenda; Thomas, Angela; Chapman, Karen

doi:10.1016/j.jpeds.2019.12.054

Cited by 5 publications

(4 citation statements)

References 14 publications

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“…As for Hydroxysteroid 11-Beta Dehydrogenase 1 HSD11B1, its translation product is a catalyst for the generation of corticosteroids. Current research believes that its function is mainly concentrated in endocrine (22,23).…”

Section: The Correlation Of Aqp9 Expression With Survival and Clinical Characteristicsmentioning

confidence: 99%

AQP9 Is a Prognostic Factor for Kidney Cancer and a Promising Indicator for M2 TAM Polarization and CD8+ T-Cell Recruitment

Jing

Sun

et al. 2021

Front. Oncol.

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BackgroundIt is undeniable that the tumor microenvironment (TME) plays an indispensable role in the progression of kidney renal clear cell carcinoma (KIRC). However, the precise mechanism of activities in TME is still unclear.Methods and ResultsUsing the CIBERSORT and ESTIMATE calculation methods, the scores of the two main fractions of tumor-infiltrating immune cells (TICs) from The Cancer Genome Atlas (TCGA) database of 537 KIRC patients were calculated. Subsequently, differentially expressed genes (DEGs) were drawn out by performing an overlap between Cox regression analysis and protein–protein interaction (PPI) network. Aquaporin 9 (AQP9) was identified as a latent predictor through the process. Following research revealed that AQP9 expression was positively correlated with the pathological characteristics (TNM stage) and negatively connected with survival time. Then, by performing gene set enrichment analysis (GSEA), it can be inferred that genes with high expression level of AQP9 were mainly enriched in immune-related activities, while low AQP9 group was associated with functions of cellular metabolism. Further studies have shown that regulatory T cells (Tregs), macrophages M2, macrophages M0, CD4+ T cells, and neutrophils were positively correlated with AQP9 expression. While the levels of mast cells, natural killer (NK) cells, and CD8+ T cells are negatively correlated with AQP9. The result of multiple immunohistochemistry (mIHC) suggests a negative relevance between AQP9 and CD8+ T cells and reveals a trend of consistent change on AQP9 and M2 macrophages.ConclusionThe expression level of AQP9 may be helpful in predicting the prognosis of patients with KIRC, especially to the TME state transition, the mechanism of which is possibly through lipid metabolism and P53, Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways that affect M2 polarization. AQP9 was associated with the expression levels of M2, tumor-associated macrophages (TAMs), and the recruitment of CD8+ T cells in tumor environment. The research result indicates that AQP9 may be an obstacle to maintain the immune activity of TME.

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Section: The Correlation Of Aqp9 Expression With Survival and Clinical Characteristicsmentioning

confidence: 99%

AQP9 Is a Prognostic Factor for Kidney Cancer and a Promising Indicator for M2 TAM Polarization and CD8+ T-Cell Recruitment

Jing

Sun

et al. 2021

Front. Oncol.

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“…82 In a subsequent study of children ALL, decreased 11β-HSD1 expression and/or increased 11β-HSD-2 expression were associated with GC resistance. 83 These studies indicate that 11β-HSD-1/2 play an important role in GCR occurrence.…”

Section: Impaired Nuclear Translocation Of the Gr Complexmentioning

confidence: 79%

“…Compared with GC‐sensitive NS patients, 11β‐HSD‐2 mRNA was increased in peripheral blood mononuclear cells of GC‐resistant patients 82 . In a subsequent study of children ALL, decreased 11β‐HSD1 expression and/or increased 11β‐HSD‐2 expression were associated with GC resistance 83 . These studies indicate that 11β‐HSD‐1/2 play an important role in GCR occurrence.…”

Section: Glucocorticoid Resistancementioning

confidence: 81%

Molecular mechanisms of glucocorticoid resistance

Huang

Wang

2022

Eur J Clin Investigation

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Background As a powerful anti‐inflammatory, immunosuppressive, and antiproliferative drug, glucocorticoid (GC) plays an important role in the treatment of various diseases. However, some patients may experience glucocorticoid resistance (GCR) in clinical, and its molecular mechanism have not been determined. Methods The authors performed a review of the literature on GCR focusing on mutations in the NR3C1 gene and impaired glucocorticoid receptor (GR) signalling, using METSTR (2000 through May 2022) to identify original articles and reviews on this topic. The search terms included ‘glucocorticoid resistance/insensitive’, ‘steroid resistance/insensitive’, ‘NR3C1’, and ‘glucocorticoid receptor’. Results Primary GCR is mainly caused by NR3C1 gene mutation, and 31 NR3C1 gene mutations have been reported so far. Secondary GCR is caused by impaired GC signalling pathways, including decreased expression of GR, impaired nuclear translocation of GR, and impaired binding of GR to GC and GR to target genes. However, the current research is more on the expression level of GR, and there are relatively few studies on other mechanisms. In addition, methods for improving GC sensitivity are rarely reported. Conclusion The molecular mechanisms of GCR are complex and may differ in different diseases or different patients. In future studies, when exploring the mechanism of GCR, methods to improve GC sensitivity should also be investigated.

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“…19 In human T-lymphoblastic leukaemia cells, both HSD11B2 expression and reciprocal regulation of HSD11B1 and HSD11B2 have been shown to be associated with glucocorticoid resistance. 20,21 Data for tissue resistance to glucocorticoid activity are limited in critical illness. Indirect evidence suggesting altered tissue HSD11B activity comes from studies that found increased plasma cortisol:cortisone ratio in critically ill septic and trauma patients.…”

Section: Discussionmentioning

confidence: 99%

Down-Regulation of the Mineralocorticoid Receptor (MR) and Up-Regulation of Hydroxysteroid 11-Beta Dehydrogenase Type 2 (HSD11B2) Isoenzyme in Critically Ill Patients

et al. 2023

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The mineralocorticoid receptor (MR) has two ligands, aldosterone and cortisol. Hydroxysteroid 11-beta dehydrogenase (HSD11B) isoenzymes regulate which ligand will bind to MR. In this study we aimed to evaluate the expression of the MR and the HSD11B isozymes in peripheral polymorphonuclear cells (PMNs) in critical illness for a 13-day period. Design: Prospective studySetting: One multi-disciplinary intensive care unit (ICU) Participants: Forty-two critically ill patients Methods: Messenger RNA (mRNA) expression of MR, HSD11B1, and HSD11B2, aldosterone levels, and plasma renin activity (PRA) were measured in 42 patients on ICU admission and on days 4, 8, and 13. Twenty-five age and sex-matched healthy subjects were used as controls.Results: Compared to healthy controls, MR expression in critically ill patients was lower during the entire study period. HSD11B1 expression was also lower, while HSD11B2 expression was higher. In patients, PRA, aldosterone, the aldosterone:renin ratio, and cortisol remained unaltered during the study period. Conclusion:Our results suggest that, in our cohort of critically ill patients, local endogenous cortisol availability is diminished, pointing towards glucocorticoid resistance. Aldosterone probably occupies the MR, raising the possibility that PMNs might be useful to study to gain insights into MR functionality during pathological states.

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Reciprocal Regulation of HSD11B1 and HSD11B2 Predicts Glucocorticoid Sensitivity in Childhood Acute Lymphoblastic Leukemia

Cited by 5 publications

References 14 publications

AQP9 Is a Prognostic Factor for Kidney Cancer and a Promising Indicator for M2 TAM Polarization and CD8+ T-Cell Recruitment

AQP9 Is a Prognostic Factor for Kidney Cancer and a Promising Indicator for M2 TAM Polarization and CD8+ T-Cell Recruitment

Molecular mechanisms of glucocorticoid resistance

Down-Regulation of the Mineralocorticoid Receptor (MR) and Up-Regulation of Hydroxysteroid 11-Beta Dehydrogenase Type 2 (HSD11B2) Isoenzyme in Critically Ill Patients

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