Refine
Has Fulltext
- yes (25)
Is part of the Bibliography
- yes (25)
Year of publication
Document Type
- Journal article (24)
- Doctoral Thesis (1)
Language
- English (25) (remove)
Keywords
- adrenocortical carcinoma (4)
- biomarker (3)
- hypercortisolism (3)
- miRNA (3)
- ACTH (2)
- CYP2W1 (2)
- Cushing’s disease (2)
- FGF-pathway (2)
- FGFR (2)
- SOAT1 (2)
- adenomas (2)
- adrenocortical tumors (2)
- carcinomas (2)
- cortisol (2)
- immune response (2)
- mitotane (2)
- ACC (1)
- Antigen 4 (1)
- Autoimmune-Diseases (1)
- BIRC7 (1)
- Blutbildendes Gewebe (1)
- CTNNB1 (1)
- CYP2B6 (1)
- Cushing's (1)
- Cushings syndrome (1)
- Cushing’s syndrome (1)
- Dendritic Cells (1)
- EMT (1)
- FGFR-inhibitors (1)
- FoxP3 Expression (1)
- IDH1/2 (1)
- Immune-System (1)
- Immunological Self-Tolerance (1)
- Medizin (1)
- Multiple-Sclerosis (1)
- NR3C1 (1)
- Persistenz (1)
- Polyomaviren (1)
- Polyomavirus JC (1)
- RNA Expression (1)
- RNAScope (1)
- SNP (1)
- Sex-Hormones (1)
- Suppressive Function (1)
- Systemic-Lupus-Erythematosus (1)
- USP8 (1)
- adrenal glands (1)
- adrenal tumor (1)
- adrenocortical adenoma (1)
- adrenocortical cancer (1)
- adrenocortical development (1)
- adrenocortical tissues (1)
- adrenocortical tumor (1)
- astrocytoma (1)
- autoantibodies (1)
- bioinformatic clustering (1)
- biomarker prediction (1)
- cancer (1)
- cancer detection (1)
- cancer diagnosis (1)
- cancer treatment (1)
- cancer-testis antigens (1)
- carcinogenesis (1)
- carcinoma (1)
- caspase-3 (1)
- catenin (1)
- cholesterol metabolism (1)
- chromosomes (1)
- circulating microRNA (1)
- comparative genomic hybridization (1)
- cortisol-producing adenoma (1)
- cytoplasmic staining (1)
- deubiquitinases (1)
- dogs (1)
- drug therapy (1)
- early prognosis (1)
- epithelial markers (1)
- expression (1)
- genetic loci (1)
- glioblastoma (1)
- glucocorticoid excess (1)
- high-resolution analysis (1)
- hormones (1)
- immunity (1)
- immunohistochemistry (1)
- immunohistochemistry techniques (1)
- immunotherapy (1)
- in silico analysis (1)
- kinase (1)
- kinases (1)
- lipid droplets (1)
- livin (1)
- lncRNA (1)
- lymphocytes (1)
- machine learning (1)
- malignant tumors (1)
- mesenchymal markers (1)
- miR-182-5p (1)
- miR-183 cluster (1)
- miR-483-5p (1)
- mutation (1)
- mutation triggers (1)
- neutral loss (1)
- normal adrenal glands (1)
- notch signaling (1)
- nuclear staining (1)
- pathogenesis (1)
- patient survival (1)
- persistierende Infektion (1)
- phosphorylation (1)
- pituitary (1)
- pituitary adenomas (1)
- pituitary gland (1)
- predictive marker (1)
- prognostic markers (1)
- prostate cancer (1)
- protein expression (1)
- recurrence (1)
- recurrence-free survival (1)
- serum (1)
- somatic mutations (1)
- surgical oncology (1)
- t-lymphocytes (1)
- targeted therapy (1)
- tumor microenvironment (1)
- tumor-infiltrating (1)
- tumors (1)
- unsupervised clustering (1)
Institute
- Medizinische Klinik und Poliklinik I (24)
- Pathologisches Institut (10)
- Comprehensive Cancer Center Mainfranken (4)
- Institut für Pharmakologie und Toxikologie (2)
- Theodor-Boveri-Institut für Biowissenschaften (2)
- Urologische Klinik und Poliklinik (2)
- Center for Computational and Theoretical Biology (1)
- Institut für Klinische Biochemie und Pathobiochemie (1)
- Institut für Rechtsmedizin (1)
- Institut für Virologie und Immunbiologie (1)
FGF/FGFR signaling regulates embryogenesis, angiogenesis, tissue homeostasis and wound repair by modulating proliferation, differentiation, survival, migration and metabolism of target cells. Understandably, compelling evidence for deregulated FGF signaling in the development and progression of different types of tumors continue to emerge and FGFR inhibitors arise as potential targeted therapeutic agents, particularly in tumors harboring aberrant FGFR signaling. There is first evidence of a dual role of the FGF/FGFR system in both organogenesis and tumorigenesis, of which this review aims to provide an overview. FGF-1 and FGF-2 are expressed in the adrenal cortex and are the most powerful mitogens for adrenocortical cells. Physiologically, they are involved in development and maintenance of the adrenal gland and bind to a family of four tyrosine kinase receptors, among which FGFR1 and FGFR4 are the most strongly expressed in the adrenal cortex. The repeatedly proven overexpression of these two FGFRs also in adrenocortical cancer is thus likely a sign of their participation in proliferation and vascularization, though the exact downstream mechanisms are not yet elucidated. Thus, FGFRs potentially offer novel therapeutic targets also for adrenocortical carcinoma, a type of cancer resistant to conventional antimitotic agents.
Context
Cushing’s syndrome (CS) is a rare disease of endogenous hypercortisolism associated with high morbidity and mortality. Diagnosis and classification of CS is still challenging.
Objective
Circulating microRNAs (miRNAs) are minimally invasive diagnostic markers. Our aim was to characterize the circulating miRNA profiles of CS patients and to identify distinct profiles between the two major CS subtypes.
Methods
We included three groups of patients from the German Cushing’s registry: ACTH-independent CS (Cortisol-Producing-Adenoma; CPA), ACTH-dependent pituitary CS (Cushing’s Disease; CD), and patients in whom CS had been ruled out (controls). Profiling of miRNAs was performed by next-generation-sequencing (NGS) in serum samples of 15 CS patients (each before and after curative surgery) and 10 controls. Significant miRNAs were first validated by qPCR in the discovery cohort and then in an independent validation cohort of 20 CS patients and 11 controls.
Results
NGS identified 411 circulating miRNAs. Differential expression of 14 miRNAs were found in the pre- and postoperative groups. qPCR in the discovery cohort validated 5 of the significant miRNAs from the preoperative group analyses. Only, miR-182-5p was found to be significantly upregulated in the CD group of the validation cohort. Comparing all CS samples as a group with the controls did not reveal any significant differences in expression.
Outcome
In conclusion, our study identified miR-182-5p as a possible biomarker for CD, which has to be validated in a prospective cohort. Furthermore, our results suggest that presence or absence of ACTH might be at least as relevant for miRNA expression as hypercortisolism itself.
MiRNAs are important epigenetic players with tissue- and disease-specific effects. In this study, our aim was to investigate the putative differential expression of miRNAs in adrenal tissues from different forms of Cushing's syndrome (CS). For this, miRNA-based next-generation sequencing was performed in adrenal tissues taken from patients with ACTH-independent cortisol-producing adrenocortical adenomas (CPA), from patients with ACTH-dependent pituitary Cushing's disease (CD) after bilateral adrenalectomy, and from control subjects. A confirmatory QPCR was also performed in adrenals from patients with other CS subtypes, such as primary bilateral macronodular hyperplasia and ectopic CS. Sequencing revealed significant differences in the miRNA profiles of CD and CPA. QPCR revealed the upregulated expression of miR-1247-5p in CPA and PBMAH (log2 fold change > 2.5, p < 0.05). MiR-379-5p was found to be upregulated in PBMAH and CD (log2 fold change > 1.8, p < 0.05). Analyses of miR-1247-5p and miR-379-5p expression in the adrenals of mice which had been exposed to short-term ACTH stimulation showed no influence on the adrenal miRNA expression profiles. For miRNA-specific target prediction, RNA-seq data from the adrenals of CPA, PBMAH, and control samples were analyzed with different bioinformatic platforms. The analyses revealed that both miR-1247-5p and miR-379-5p target specific genes in the WNT signaling pathway. In conclusion, this study identified distinct adrenal miRNAs as being associated with CS subtypes.
Somatic mutations in protein kinase A catalytic α subunit (PRKACA) were found to be causative for 30-40% of cortisol-producing adenomas (CPA) of the adrenal gland, rendering PKA signalling constitutively active. In its resting state, PKA is a stable and inactive heterotetramer, consisting of two catalytic and two regulatory subunits with the latter inhibiting PKA activity. The human genome encodes three different PKA catalytic subunits and four different regulatory subunits that are preferentially expressed in different organs. In normal adrenal glands all regulatory subunits are expressed, while CPA exhibit reduced protein levels of the regulatory subunit IIβ. In this study, we linked for the first time the loss of RIIβ protein levels to the PRKACA mutation status and found the down-regulation of RIIβ to arise post-transcriptionally. We further found the PKA subunit expression pattern of different tumours is also present in the zones of the normal adrenal cortex and demonstrate that the different PKA subunits have a differential expression pattern in each zone of the normal adrenal gland, indicating potential specific roles of these subunits in the regulation of different hormones secretion.
Mutations in the PRKACA gene are the most frequent cause of cortisol-producing adrenocortical adenomas leading to Cushing’s syndrome. PRKACA encodes for the catalytic subunit α of protein kinase A (PKA). We already showed that PRKACA mutations lead to impairment of regulatory (R) subunit binding. Furthermore, PRKACA mutations are associated with reduced RIIβ protein levels; however, the mechanisms leading to reduced RIIβ levels are presently unknown. Here, we investigate the effects of the most frequent PRKACA mutation, L206R, on regulatory subunit stability. We find that Ser\(^{114}\) phosphorylation of RIIβ is required for its degradation, mediated by caspase 16. Last, we show that the resulting reduction in RIIβ protein levels leads to increased cortisol secretion in adrenocortical cells. These findings reveal the molecular mechanisms and pathophysiological relevance of the R subunit degradation caused by PRKACA mutations, adding another dimension to the deregulation of PKA signaling caused by PRKACA mutations in adrenal Cushing’s syndrome.