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Adrenal tumors, such as adrenocortical carcinoma (ACC), adrenocortical adenoma (ACA), and pheochromocytoma (PCC) are complex diseases with unclear causes and treatments. Mitochondria and mitochondrial-derived peptides (MDPs) are crucial for cancer cell survival. The primary aim of this study was to analyze samples from different adrenal diseases, adrenocortical carcinoma, adrenocortical adenoma, and pheochromocytoma, and compare them with normal adrenal tissue to determine whether the expression levels of the mitochondrial open reading frame of the 12S rRNA type-c (MOTS-c) gene and protein vary between different types of adrenal tumors compared to healthy controls using qPCR, ELISA, and IHC methods. Results showed decreased MOTS-c mRNA expression in all adrenal tumors compared to controls, while serum MOTS-c protein levels increased in ACA and PCC but not in ACC. The local distribution of MOTS-c protein in adrenal tissue was reduced in all tumors. Notably, MOTS-c protein expression declined with ACC progression (stages III and IV) but was unrelated to patient age or sex. Tumor size and testosterone levels positively correlated with MOTS-c mRNA but negatively with serum MOTS-c protein. Additionally, serum MOTS-c protein correlated positively with glucose, total cholesterol, HDL, LDL, and SHGB levels. These findings suggest disrupted expression of MOTS-c in the spectrum of adrenal diseases, which might be caused by mechanisms involving increased mitochondrial dysfunction and structural changes in the tissue associated with disease progression. This study provides a detailed examination of MOTS-c mRNA and protein in adrenal tumors, indicating the potential role of MDPs in tumor biology and progression. [ABSTRACT FROM AUTHOR]

The aim of the study was to evaluate the diagnostic and prognostic significance of leptin receptor isoforms in adrenal tumors. In a single-center study, 96 patients (19 with adrenal cortical carcinoma and 77 with benign tumors) underwent an adrenalectomy. A total of 14 unaffected adrenal gland tissues from kidney donors were used as controls. Fasting blood samples were collected for laboratory tests, and mRNA expressions of leptin receptor isoforms were assessed by RT-qPCR. The study analyzed correlations between mRNA expressions and clinical data and measured NCI-H295R cell proliferation via a real-time cell analyzer. All adrenal lesions expressed leptin receptor isoforms. Significantly lower LepR1 expression was observed in carcinoma tissues than in adenomas and controls (p = 0.016). Expressions of LepR3&LepR6 were correlated with overall survival (p = 0.036), while LepR2&LepR4 and LepR5 expressions were inversely related to morning serum cortisol levels (p = 0.041). Leptin reduced NCI-H295R cell proliferation (p < 0.0001). The study highlights the diagnostic and prognostic significance of leptin receptor isoforms in adrenal tumors. Specifically, LepR1 may serve as a diagnostic marker for carcinomas, while LepR3&LepR6 have potential use as prognostic markers. [ABSTRACT FROM AUTHOR]

The discovery of mitochondria-derived peptides (MDPs) has provided a new perspective on mitochondrial function. MDPs encoded by mitochondrial DNA (mtDNA) can act as hormone-like peptides, influencing cell survival and proliferation. Among these peptides, humanin has been identified as a crucial factor for maintaining cell survival and preventing cell death under various conditions. Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy that results from adrenal hormone dysfunction. This study aimed to investigate humanin expression in the adrenal tissue and serum of patients with ACC. For the first time, our study revealed significant reduction in the mRNA expression of humanin in patients with ACC compared to healthy controls. However, no significant changes were observed in the serum humanin levels. Interestingly, we identified a positive correlation between patient age and serum humanin levels and a negative correlation between tumor size and LDL levels. While the impaired expression of humanin in patients with ACC may be attributed to mitochondrial dysfunction, an alternative explanation could be related to diminished mitochondrial copy number. Further investigations are warranted to elucidate the intricate relationship among humanin, mitochondrial function, and ACC pathology. [ABSTRACT FROM AUTHOR]

Zwilch kinetochore protein (ZWILCH) plays a key role in proper cell proliferation. The upregulation of the ZWILCH gene was observed in many types of cancers, but the association of ZWILCH with adrenocortical carcinoma (ACC) was not investigated so far. The main aim of the presented study was to verify if the enhanced level of the ZWILCH gene can be used as a diagnostic marker for ACC development and progression, as well as a predictor of survival time for ACC patients. The performed analyses included investigation of the ZWILCH expression profile in tumors with publicly available TCGA (The Cancer Genome Atlas) datasets and transcriptomic data from the Gene Expression Omnibus (GEO) database, as well as, in human biological samples of normal adrenal, adrenocortical carcinoma and in commercially available tissue microarrays. The findings demonstrate statistically significant higher ZWILCH gene expression in ACC tissue in comparison with normal adrenal glands. Furthermore, there is a strong correlation between ZWILCH upregulation and tumor mitotic rate and the probability of patient survival. The enhanced ZWILCH level is also connected with the activation of genes involved in cell proliferation and the inhibition of genes related to the immune system. This work contributes to a better understanding of the role of ZWILCH as an ACC biomarker and diagnostic tool. [ABSTRACT FROM AUTHOR]

Adrenocortical carcinomas (ACC) are rare endocrine malignancies, often with a poor prognosis. Visfatin/NAMPT regulates a variety of signaling pathway components, and its overexpression has been found in carcinogenesis. Our study aimed to assess the clinical usefulness of visfatin/NAMPT serum level in discriminating between ACC and benign adrenocortical tumors. Twenty-two patients with ACC and twenty-six patients with benign adrenocortical tumors were recruited. Fasting blood samples were collected from each patient, and visfatin serum levels were measured with the ELISA Kit. Clinical stage, tumor size, Ki67 proliferation index, hormonal secretion pattern, and follow-up were determined in ACC patients. Patients with ACC had significantly higher visfatin serum concentrations (7.81 ± 2.25 vs. 6.08 ± 1.32 ng/mL, p-value = 0.003). The most advanced clinical stage with metastases was associated with significantly elevated visfatin levels (p-value = 0.022). Based on ROC analysis, visfatin serum concentrations higher than 8.05 ng/mL could discriminate ACC with a sensitivity of 50.0% and specificity of 92.3%. Univariate Cox regression indicated that tumor size was significantly related to shorter survival, and the visfatin level was borderline significant in all patients (HR = 1.013, p-value = 0.002, HR = 1.321, p-value = 0.058). In the Kaplan-Meier method, patients with visfatin serum concentrations higher than 6.3 ng/mL presented significantly lower survival probability (p-value = 0.006). Serum visfatin/NAMPT could be a potential risk predictor for the malignancy of adrenal tumors. However, further studies are needed on this subject. [ABSTRACT FROM AUTHOR]

Introduction. Ghrelin, originally isolated from the endocrine cells of the gastric mucosa, is also expressed in many peripheral tissues, including normal adrenals and adrenocortical tumors. It was shown that ghrelin stimulates proliferation and inhibits apoptosis of adrenocortical cells. In the current study, we compared ghrelin expression at the protein level in various adrenal tumors. We analyzed whether immunoreactive ghrelin could be considered as a potential marker for different types of adrenal tumors. Material and methods. Study was carried out on 200 adrenal specimens arranged on microscope slide in tissue microarray format. We performed standardized immunohistochemical reactions with semiquantitative reaction intensity measurements. Results. At the protein level, the expression of ghrelin was significantly reduced in adrenocortical adenocarcinoma in relation to the control group and pheochromocytoma as well as cancer-adjacent normal adrenal tissue. In contrast, a relatively high ghrelin expression was found in pheochromocytoma compared to all analyzed groups, with the exception of cancer-adjacent normal adrenal tissue. Conclusions. The ghrelin expression profile at the protein level may be associated with the type of adrenal tumor. In this context, our results suggest that adrenal immunoreactive ghrelin may be considered as a sensitive and specific marker for differentiating adrenocortical carcinoma from adrenocortical adenoma and pheochromocytoma. [ABSTRACT FROM AUTHOR]

Adropin is a multifunctional peptide hormone encoded by the ENHO (energy homeostasis associated) gene. It plays a role in mechanisms related to increased adiposity, insulin resistance, as well as glucose, and lipid metabolism. The low adropin levels are strongly associated with obesity independent insulin resistance. On the other hand, overexpression or exogenous administration of adropin improves glucose homeostasis. The multidirectional, adropin-related effects associated with the regulation of metabolism in humans also appear to be attributable to the effects of this peptide on the activity of various elements of the endocrine system including adrenal cortex. Therefore, the main purpose of the present study was to investigate the effect of adropin on proliferation and secretory activity in the human HAC15 adrenal carcinoma cell line. In this study, we obtained several highly interesting findings. First, GPR19, the main candidate sensitizer of adrenocortical cells to adropin, was expressed in HAC15 cells. Moreover, GPR19 expression was relatively stable and not regulated by ACTH, forskolin, or adropin itself. Our findings also suggest that adropin has the capacity to decrease expression levels of steroidogenic genes such as steroidogenic acute regulatory protein (StAR) and CYP11A1 , which then led to a statistically significant inhibition in cortisol and aldosterone biosynthesis and secretion. Based on whole transcriptome study and research involving transforming growth factor (TGF)-β type I receptor kinase inhibitor we demonstrated that attenuation of steroidogenesis caused by adropin is mediated by the TGF-β signaling pathway likely to act through transactivation mechanism. We found that HAC15 cells treated with adropin presented significantly higher proliferation levels than untreated cells. Using specific intracellular inhibitors, we showed that adropin stimulate proliferation via ERK1/2 and AKT dependent signaling pathways. We have also demonstrated that expression of GPR19 is elevated in adrenocortical carcinoma in relation to normal adrenal glands. High level of GPR19 expression in adrenocortical carcinoma may constitute a negative prognostic factor of disease progression. [ABSTRACT FROM AUTHOR]

Background. Galanin-like peptide (Galp) and alarin (Ala) are 2 new members of the galanin peptide family. Galanin (Gal), the "parental" peptide of the entire family, is known to regulate numerous physiological processes, including energy and osmotic homeostasis, reproduction, food intake, and secretion of adrenocortical hormones. Galp and Ala are known to regulate food intake. In the rat, Galp mRNA has been found in the brain, exclusively in the hypothalamic arcuate nucleus (ARC) and median eminence, which are involved in the regulation of energy homeostasis. Alarin-like immunoreactivity is present in the locus coeruleus (LC) and the ARC of rats and mice. Objectives. The aim of the study was to investigate the expression of Ala, Galp and their receptors in the organs of the hypothalamo-pituitary-adrenal (HPA) axis of the rat. Material and methods. The expression of the examined genes was measured in different models of adrenal growth of the rat in vivo (postnatal ontogenesis, compensatory adrenal growth, adrenocortical regeneration, adrenocorticotropic hormone (ACTH) administration). The expression was evaluated using the Affymetrix® microarray system or quantitative polymerase chain reaction (qPCR). Results. The expression of Ala gene was observed in each organ of the HPA axis (the hypothalamus, hypophysis and adrenal gland). The elevated level of expression of this gene was observed in the pituitary of 2-day rats, while very low levels of Ala mRNA were observed in the adrenals. Galp mRNA expression was observed only in the hypothalamus and the hypophysis during postnatal ontogenesis. The expression of Gal receptors was demonstrated in the hypothalamus, the hypophysis and the adrenal gland. In different compartments of the adrenal glands of adult, intact male and female rats, the expression of Ala, Galp and galanin receptor 1 (Galr1) genes was negligible, but the expression of galanin receptor 2 (Galr2), galanin receptor 3 (Galr3) and neurotrophic receptor tyrosine kinase 2 (Ntrk2) genes was noticeable. Conclusions. The examined genes showed different expression levels within the studied HPA axis; some of them were neither expressed in the hypothalamus or the pituitary gland, nor in the adrenal gland. [ABSTRACT FROM AUTHOR]

Background. Ghrelin is a hormone that occurs in acylated (AG) or unacylated (UG) form. Ghrelin strongly stimulates growth hormone (GH) secretion from anterior pituitary, as well as regulates the energy balance and various metabolic parameters. Increased consideration is given to UG, thought to be inactive. Objectives. We aimed to evaluate the levels of total ghrelin, AG and UG in medically naive and treated patients with biochemically active acromegaly, with respect to variables of lipid and glucose metabolism. Material and methods. We studied total ghrelin, AG and calculated UG levels in a group of 24 patients with active acromegaly and 15 healthy controls. Plasma levels of GH, insulin-like growth factor 1 (IGF-1), insulin, glucose, total cholesterol (TC), high-density lipoprotein (HDL) cholesterol and calculated low-density lipoprotein (LDL) cholesterol, triglycerides (TG), apolipoproteins A1 (APO A1), and B-100 (APO B-100) were measured. Results. Patients with acromegaly revealed lower levels of total ghrelin than healthy controls. In pooled data of all subgroups, simple linear regression analysis revealed that total ghrelin concentration was significantly associated with APO A1 concentration (ß = 0.8087; p = 0.0315) and AG concentration was significantly associated with fasting insulin concentration (ß = 15.5183; p = 0.011). There was an inverse association between UG and the patients' age, and positive association between UG and APO A1. Conclusions. Our results suggest that ghrelin may influences metabolic disturbances in acromegaly. It seems that the assessment of AG and UG is superior to total ghrelin measurement. Mechanisms regulating ghrelin acylation and function of each form need elucidation in order to improve diagnostics and treatment of metabolic disturbances, not only acromegaly. [ABSTRACT FROM AUTHOR]

Summary: Context: Adrenal tumours belong to one of the most prevalent neoplasms. It is a heterogeneous group with different aetiology, clinical manifestation and prognosis. Its histopathologic diagnosis is difficult and identification of differentiation markers for tumorigenesis is extremely valuable for diagnosis. Design: To assess ghrelin expression and the relationship among ghrelin, IGF2 and the clinicopathological characteristics of adrenal tumours. To investigate the influence of ghrelin on ACC cell line proliferation. Materials and methods: Expression of ghrelin and IGF2 in a total of 84 adrenal tissue samples (30 adenoma, 12 hyperplasia, 8 myelolipoma, 20 pheochromocytoma, 7 carcinoma and 7 unchanged adrenal glands) were estimated. Every operated patient from whom samples were obtained underwent clinicopathological analysis. All the parameters were compared among the groups examined and correlations between these were estimated. H295R cell line was incubated with ghrelin to assess its effect on proliferation and migration rate. Results: The highest ghrelin expression was observed in carcinoma samples and the lowest in the control group. Ghrelin expression was 21 times higher in carcinoma (P = .017) and 2.4 times higher in adenoma (P = .029) compared with controls. There were no statistically significant differences between myelolipoma (P = .093) and pheochromocytoma (P = .204) relative to the control. Ghrelin level was significantly higher in carcinoma compared to adenoma (P = .049) samples. A positive correlation between ghrelin and IGF2 expression was observed only in myelolipoma (P = .001). Ghrelin at concentrations of 1 × 10−6 mol/L and 1 × 10−8 mol/L significantly stimulated proliferation and migration rate in the H295R cell line. Conclusion: Ghrelin appears to be an essential factor in driving adrenal tumours development. [ABSTRACT FROM AUTHOR]

Epithelioid angiomyolipoma (EAML) is a rare mesenchymal neoplasmic variant of angiomyolipoma characterized by aggressive growth and unpredictable outcome. Cases of local recurrence and distant metastasis have been described. The histopathological diagnosis may be difficult, as EAML often mimics other neoplasms. This is the case report of a 39-year-old male patient with EAML, which was initially diagnosed as adrenal cortical carcinoma, due to the lack of cooperation between clinicians and pathologists. [ABSTRACT FROM AUTHOR]

NUCB2/nesfatin and its proteolytically cleaved product nesfatin-1 are recently discovered anorexigenic hypothalamic neuroproteins involved in energy homeostasis. It is expressed both centrally and in peripheral tissues, and appears to have potent metabolic actions. NUCB2/nesfatin neurons are activated in response to stress. Central nesfatin-1 administration elevates circulating ACTH and corticosterone levels. Bilateral adrenalectomy increased NUCB2/nesfatin mRNA levels in rat paraventricular nuclei. To date, studies have not assessed the effects of nesfatin-1 stimulation on human adrenocortical cells. Therefore, we investigated the expression and effects of nesfatin-1 in a human adrenocortical cell model (H295R). Our findings demonstrate that NUCB2 and nesfatin-1 are expressed in human adrenal gland and human adrenocortical cells (H295R). Stimulation with nesfatin-1 inhibits the growth of H295R cells and promotes apoptosis, potentially via the involvement of Bax, BCL-XL and BCL-2 genes as well as ERK1/2, p38 and JNK1/2 signalling cascades. This has implications for understanding the role of NUCB2/nesfatin in adrenal zonal development. NUCB2/nesfatin may also be a therapeutic target for adrenal cancer. However, further studies using in vivo models are needed to clarify these concepts. [ABSTRACT FROM AUTHOR]

Neuroendocrine tumours may be associated with familial syndromes. At least eight inherited syndromes predisposing to endocrine neoplasia have been identified. Two of these are considered to be major factors predisposing to benign and malignant endocrine tumours, designated multiple endocrine neoplasia type 1 and type 2 (MEN1 and MEN2). Five other autosomal dominant diseases show more heterogeneous clinical patterns, such as the Carney complex, hyperparathyroidism-jaw tumour syndrome, Von Hippel-Lindau syndrome (VHL), neurofibromatosis type 1 (NF1) and tuberous sclerosis. The molecular and cellular interactions underlying the development of most endocrine cells and related organs represent one of the more complex pathways not yet to be deciphered. Almost all endocrine cells are derived from the endoderm and neuroectoderm. It is suggested that within the first few weeks of human development there are complex interactions between, firstly, the major genes involved in the initiation of progenitor-cell differentiation, secondly, factors secreted by the surrounding mesenchyme, and thirdly, a series of genes controlling cell differentiation, proliferation and migration. Together these represent a formula for the harmonious development of endocrine glands and tissue. [ABSTRACT FROM AUTHOR]

A previous case report described an adrenal incidentaloma initially misdiagnosed as adrenocortical carcinoma (ACC), which was treated with mitotane. The final diagnosis was metastatic melanoma of unknown primary origin. However, the patient developed rapid disease progression after mitotane withdrawal, suggesting a protective role for mitotane in a non-adrenal-derived tumor. The aim of the present study was to determine the biological response of primary melanoma cells obtained from that patient, and that of other established melanoma and ACC cell lines, to mitotane treatment using a proliferation assay, flow cytometry, quantitative PCR and microarrays. Although mitotane inhibited the proliferation of both ACC and melanoma cells, its role in melanoma treatment appears to be limited. Flow cytometry analysis and transcriptomic studies indicated that the ACC cell line was highly responsive to mitotane treatment, while the primary melanoma cells showed a moderate response in vitro. Mitotane modified the activity of several key biological processes, including 'mitotic nuclear division', 'DNA repair', 'angiogenesis' and 'negative regulation of ERK1 and ERK2 cascade'. Mitotane administration led to elevated levels of DNA double-strand breaks, necrosis and apoptosis. The present study provides a comprehensive insight into the biological response of mitotane-treated cells at the molecular level. Notably, the present findings offer new knowledge on the effects of mitotane on ACC and melanoma cells. [ABSTRACT FROM AUTHOR]