A glukokortikoid receptor izoformák szerepe a mellékvesekéreg daganatok patogenesisében = Role of the glucocorticoid receptor isoforms in the pathogenesis of adrenocortical tumors

1-es célkitűzés: Az N363S gyakoribb míg az A3669G ritkább előfordulási gyakoriságát igazoltuk hormonálisan inaktív mellékvese adenómás betegekben a kontroll populációhoz képest. Ez az összefüggés még erősebb volt kétoldali adenómásokban. Genotípus-fenotípus összefüggések: az N363S a 2-es típusú diabetes mellitussal, az A3669G magasabb testsúllyal és BMI-vel, a BclI pedig emelkedett szisztolés vérnyomással és magasabb koleszterin értékkel mutatott összefüggést. 2-es célkitűzés: a normális mellékvesekéreghez képest a kortizolt termelő szövetekben (CPA) fokozott GRalfa és GRbéte expressziót igazoltunk mind fehérje, mind pedig mRNS szinten. Immunhisztokémiával a GRbéta erős citoplazmatikus és sejtmagi festődését mutattuk ki a CPA-ban. 3-as célkitűzés: A 47 nukleáris kofaktor és 12 koaktivátor közül csak a HSP90B, NR2F1 volt alulexpresszálódó a CPA szövetekben, míg az RARB a hormonálisan inaktív daganatokban. Fokozott expressziót csak az NRoB1 mutatott a CPA szövetekben. Dexamethasone kezelésre a H295R sejtvonalban 17 kofaktor expressziója változottt. 4-es célkitűzés: létrehoztunk egy sejtvonalat a Caco-2GRbeta-t, ami stabilan expresszálja a GRalfa-val összemérhető mennyiségben a receptor béta izoformáját. Teljes genom génexpressziós vizsgálat alapján a béta izoformának géntranszkripciós aktivitása lehet. | Objective 1: The carrier frequency of the N363S was higher while the prevalence of A3669G (located in GRbeta) was lower in hormonally inactive (HI) than in healthy population. These associations were even stronger in patients with bilateral HI tumors. Genotype-phenotype associations: the N363S polymorphism associated with type 2 diabetes mellitus, the polymorphism A3669G associated with higher body weight and body mass index and the BclI polymorphisms of the GR associated with higher systolic blood pressure and higher cholesterol level in patietns with adrenal incidentalomas. Objective 2: Compared to normal adrenocortical tissues, both GR? and GR? mRNAs were significantly increased in cortisol producing adenomas (CPA) whereas GR?, but not GR? mRNA expression was moderately increased in HI. GR? immunostaining was absent in normal adrenal tissues and HI, while a strong cytoplasmic and nuclear immunoreaction was found in CPA Objective 3: Of 47 nuclear receptors and 12 coactivators we found 2 genes (HSP90B, NR2F1) significantly underexpresed in CPA and only the RARB was underexpressed in HI compared to normal tissue. Only one (NR0B1) was overexpressed in CPA compared to normal tissue. Expression of 17 nuclear cofactors and corepressors changed after Dex treatment in H295R cell line. Objective 4: We developed a cell line stably expressing the GR? isoform. Whole genome gene expression analysis showed that the GR? itself regulates gene transcription

MicroRNAs in endocrine tumors.

MicroRNAs (miRNAs) are small, protein noncoding RNAs that regulate gene expression post-transcriptionally. Their role is considered to set the gene expression to the optimal level, or in other words to provide "fine tuning" of gene expression. They regulate essential physiological processes such as differentiation, cell growth, apoptosis and their role is known in tumor development too. At tissue level differential miRNA expression in endocrine disorders including endocrine malignancies has also been reported. A new era of miRNAs-related research started when miRNAs were successfully detected outside of cells, in biofluids, in cell-free environments. Their significant role has been demonstrated in cell-cell communication in tumor biology. Due to their stability circulating miRNAs can serve as potential biomarkers. In common diseases circulating miRNAs can be potentially proposed as screening biomarkers and they are also useful to detect tumor recurrence hence they can be applied in post-surgery follow-up too. MiRNAs as diagnostic markers can also be helpful at tissue level when certain histology diagnosis is challenging. Beside diagnosis, tissue miRNAs have the potential to predict prognosis. Intensive research is carried out regarding endocrine tumors as well in terms of miRNAs. However, until now miRNAs as biomarkers do not applied in routine diagnostics, probably due to the challenging preanalytics. In this review we summarized tissue and circulating miRNAs found in thyroid, adrenal, pituitary and neuroendocrine tumors. We aimed to highlight the most important, selected miRNAs with potential diagnostic and prognostic value both in tissue and circulation. Common miRNAs across different endocrine neoplasms are summarized and miRNAs enriched at 14q31 locus are also highlighted suggesting their general role in tumorigenesis of endocrine glands

Mechanisms Behind Context-Dependent Role of Glucocorticoids in Breast Cancer Progression

Glucocorticoids (GCs), mostly dexamethasone (dex), are routinely administered as adjuvant therapy to manage side effects in breast cancer. However, recently, it has been revealed that dex triggers different effects and correlates with opposite outcomes depending on the breast cancer molecular subtype. This has raised new concerns regarding the generalized use of GC and suggested that the context-dependent effects of GCs can be taken into potential consideration during treatment design. Based on this, attention has recently been drawn to the role of the glucocorticoid receptor (GR) in development and progression of breast cancer. Therefore, in this comprehensive review, we aimed to summarize the different mechanisms behind different context-dependent GC actions in breast cancer by applying a multilevel examination, starting from the association of variants of the GR-encoding gene to expression at the mRNA and protein level of the receptor, and its interactions with other factors influencing GC action in breast cancer. The role of GCs in chemosensitivity and chemoresistance observed during breast cancer therapy is discussed. In addition, experiences using GC targeting therapeutic options (already used and investigated in preclinical and clinical trials), such as classic GC dexamethasone, selective glucocorticoid receptor agonists and modulators, the GC antagonist mifepristone, and GR coregulators, are also summarized. Evidence presented can aid a better understanding of the biology of context-dependent GC action that can lead to further advances in the personalized therapy of breast cancer by the evaluation of GR along with the conventional estrogen receptor (ER) and progesterone receptor (PR) in the routine diagnostic procedure. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10555-022-10047-1

Biokémiai markerek jelentősége a neuroendokrin daganatok felismeresében és a betegek követésében

Circulating markers of neuroendocrine tumours are useful tools in the diagnosis of these tumours. Laboratory tests for general biomarkers have acceptable sensitivity for the recognition of neuroendocrine tumours as these biologically active proteins are typically synthesized by all types of neuroendocrine cells. Measurement of chromogranin A is widely used not only in the diagnosis of neuroendocrine tumours but it may predict the prognosis of the diseases and the effect of the antitumor therapy. It is also a useful tool for the detection of residual tumours. Neurendocrine tumours represent a heterogeneous group of tumours with the ability to secrete several hormones and, therefore, measurement of these hormones can also serve as neuroendocrine cell type-specific markers in routine clinical practice. In this review the authors summarize the significance of tumour markers in the diagnosis of neuroendocrine tumours as well as in the management and follow-up of patients with this disease. Orv. Hetil., 2014, 155(45), 1775-1782