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1.
Nucleic Acids Res ; 48(W1): W252-W261, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32319523

RESUMO

MicroRNAs (miRNAs) are small non-coding RNAs that are involved in the regulation of major pathways in eukaryotic cells through their binding to and repression of multiple mRNAs. With high-throughput methodologies, various outcomes can be measured that produce long lists of miRNAs that are often difficult to interpret. A common question is: after differential expression or phenotypic screening of miRNA mimics, which miRNA should be chosen for further investigation? Here, we present miRViz (http://mirviz.prabi.fr/), a webserver application designed to visualize and interpret large miRNA datasets, with no need for programming skills. MiRViz has two main goals: (i) to help biologists to raise data-driven hypotheses and (ii) to share miRNA datasets in a straightforward way through publishable quality data representation, with emphasis on relevant groups of miRNAs. MiRViz can currently handle datasets from 11 eukaryotic species. We present real-case applications of miRViz, and provide both datasets and procedures to reproduce the corresponding figures. MiRViz offers rapid identification of miRNA families, as demonstrated here for the miRNA-320 family, which is significantly exported in exosomes of colon cancer cells. We also visually highlight a group of miRNAs associated with pluripotency that is particularly active in control of a breast cancer stem-cell population in culture.


Assuntos
MicroRNAs/metabolismo , Software , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/metabolismo , Neoplasias do Córtex Suprarrenal/mortalidade , Carcinoma Adrenocortical/genética , Carcinoma Adrenocortical/metabolismo , Carcinoma Adrenocortical/mortalidade , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Conjuntos de Dados como Assunto , Exossomos/metabolismo , Feminino , Humanos , Internet , Camundongos , MicroRNAs/genética , Células-Tronco Neoplásicas/metabolismo
2.
Horm Metab Res ; 52(3): 133-141, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32215884

RESUMO

Primary or adrenocorticotropin-independent adrenocortical tumors and hyperplasias represent a heterogeneous group of adrenocortical neoplasms that arise from various genetic defects, either in isolation or familial. The traditional classification as adenomas, hyperplasias, and carcinomas is non-specific. The recent identification of various germline and somatic genes in the development of primary adrenocortical hyperplasias has provided important new insights into the molecular pathogenesis of adrenal diseases. In this new era of personalized care and genetics, a gene-based classification that is more specific is required to assist in the understanding of their disease processes, hormonal functionality and signaling pathways. Additionally, a gene-based classification carries implications for treatment, genetic counseling and screening of asymptomatic family members. In this review, we discuss the genetics of benign adrenocorticotropin-independent adrenocortical hyperplasias, and propose a new gene-based classification system and diagnostic algorithm that may aid the clinician in prioritizing genetic testing, screening and counseling of affected, at risk individuals and their relatives.


Assuntos
Doenças do Córtex Suprarrenal/genética , Hiperplasia/genética , Doenças do Córtex Suprarrenal/diagnóstico , Doenças do Córtex Suprarrenal/tratamento farmacológico , Doenças do Córtex Suprarrenal/metabolismo , Neoplasias do Córtex Suprarrenal/diagnóstico , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/metabolismo , Hormônio Adrenocorticotrópico/metabolismo , Aconselhamento Genético , Humanos , Hiperplasia/diagnóstico , Hiperplasia/tratamento farmacológico , Hiperplasia/metabolismo
3.
Best Pract Res Clin Endocrinol Metab ; 34(2): 101375, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32007424

RESUMO

Primary aldosteronism (PA) is the most common form of secondary hypertension affecting 5%-10% of patients with arterial hypertension. In PA, high blood pressure is associated with high aldosterone and low renin levels, and often hypokalemia. In a majority of cases, autonomous aldosterone production by the adrenal gland is caused by an aldosterone producing adenoma (APA) or bilateral adrenal hyperplasia (BAH). During the last ten years, a better knowledge of the pathophysiology of PA came from the discovery of somatic and germline mutations in different genes in both sporadic and familial forms of the disease. Those genes code for ion channels and pumps, as well as proteins involved in adrenal cortex development and function. Targeted next generation sequencing following immunohistochemistry guided detection of aldosterone synthase expression allows detection of somatic mutations in up to 90% of APA, while whole exome sequencing has discovered the genetic causes of four different familial forms of PA. The identification, in BAH, of somatic mutations in aldosterone producing cell clusters open new perspectives in our understanding of the bilateral form of the disease and the development of new therapeutic approaches.


Assuntos
Estudos de Associação Genética , Hiperaldosteronismo/genética , Neoplasias do Córtex Suprarrenal/complicações , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/metabolismo , Adenoma Adrenocortical/complicações , Adenoma Adrenocortical/genética , Adenoma Adrenocortical/metabolismo , Aldosterona/sangue , Estudos de Associação Genética/métodos , Estudos de Associação Genética/tendências , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequenciamento de Nucleotídeos em Larga Escala/tendências , Humanos , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/terapia , Hipertensão/genética
4.
Dis Markers ; 2020: 5354825, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31998416

RESUMO

Background: Adrenocortical carcinoma (ACC) is a rare malignant endocrine tumor with a high tumor recurrence rate and poor postoperative survival. Recent studies suggest that CD276- (B7-H3) targeted therapy represents a promising therapeutic option for solid tumors. However, little is known about the expression status of CD276 or its association with progression and prognosis of ACC. Methods: Clinical data were retrospectively analyzed from patients who underwent resection of ACC at our institution (n = 48). Archived, formalin-fixed, and paraffin-embedded samples were collected for immunohistochemical analysis, and the correlation between CD276 expression and clinicopathological parameters was evaluated. Kaplan-Meier and univariate/multivariate Cox regression methods were implemented to identify any prognostic effects. Data from The Cancer Genome Atlas (TCGA) ACC cohort (n = 48). Archived, formalin-fixed, and paraffin-embedded samples were collected for immunohistochemical analysis, and the correlation between CD276 expression and clinicopathological parameters was evaluated. Kaplan-Meier and univariate/multivariate Cox regression methods were implemented to identify any prognostic effects. Data from The Cancer Genome Atlas (TCGA) ACC cohort (. Results: Positive expression of CD276 was detected on the cell membrane and in the cytoplasm of cancer cells or tumor-associated vascular cells in 91.67% (44/48) of ACCs. Vascular expression of CD276 was associated with local aggression (higher T stage, P = 0.029) and advanced ENSAT stage (P = 0.029) and advanced ENSAT stage (P = 0.029) and advanced ENSAT stage (P = 0.029) and advanced ENSAT stage (P = 0.029) and advanced ENSAT stage (P = 0.029) and advanced ENSAT stage (. Conclusion: These findings highlight the immune checkpoint factor CD276 as an independent prognostic factor and a potential therapeutic target in ACC.


Assuntos
Neoplasias do Córtex Suprarrenal/metabolismo , Carcinoma Adrenocortical/metabolismo , Antígenos B7/genética , Biomarcadores Tumorais/genética , Neoplasias do Córtex Suprarrenal/diagnóstico , Neoplasias do Córtex Suprarrenal/genética , Carcinoma Adrenocortical/diagnóstico , Carcinoma Adrenocortical/genética , Adulto , Antígenos B7/metabolismo , Biomarcadores Tumorais/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
5.
Hypertension ; 75(2): 492-499, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31865789

RESUMO

The endoplasmic reticulum (ER) plays a pivotal role in syntheses of proteins and steroid hormones and regulation of intracellular Ca2+ level. We aimed to investigate ER-associated genes in aldosterone-producing adenomas (APAs) and clarify their effect on aldosterone production. Microarray analysis targeting 288 ER-associated genes was conducted using nonfunctioning adrenocortical adenomas (n=5) and APAs (n=19). Immunohistochemistry and quantitative polymerase chain reaction analyses were performed with 13 nonfunctioning adrenocortical adenoma and 48 APA samples. Functional studies were performed with human adrenocortical carcinoma (HAC15) cells, some of which were genetically modified using lentiviruses. The ER chaperone calmegin (CLGN) was the most highly expressed ER-associated gene in APAs relative to nonfunctioning adrenocortical adenomas. Analysis with quantitative polymerase chain reaction revealed CLGN to be 9.5-fold upregulated in APAs relative to nonfunctioning adrenocortical adenomas. There were no differences among different APA genotypes affecting aldosterone production. Immunohistochemistry analysis revealed that CLGN was strongly expressed in APAs and aldosterone-producing cell clusters. Angiotensin II stimulation or KCNJ5 T158A overexpression in HAC15 cells did not affect CLGN mRNA levels. CLGN overexpression in HAC15 cells increased aldosterone levels but did not stimulate CYP11B2 mRNA levels. Pathway and gene ontology analyses using RNA sequencing results showed that tRNA aminoacyl metabolism was the most enriched pathway in CLGN-overexpressing cells. CYP11B2 (aldosterone synthase) and HSD3B2 (3 beta-hydroxysteroid dehydrogenase/delta 5->4-isomerase type 2) protein expression were more abundant in CLGN-overexpressing cells. CLGN knockdown using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9) method in HAC15 cells that carry the KCNJ5 mutation did not affect aldosterone production. To summarize, CLGN was upregulated and associated with aldosterone production via translational regulation of CYP11B2 in APAs.


Assuntos
Neoplasias do Córtex Suprarrenal/genética , Adenoma Adrenocortical/genética , Aldosterona/metabolismo , Proteínas de Ligação ao Cálcio/genética , Retículo Endoplasmático/metabolismo , Regulação Neoplásica da Expressão Gênica , Chaperonas Moleculares/genética , Neoplasias Experimentais , Neoplasias do Córtex Suprarrenal/metabolismo , Neoplasias do Córtex Suprarrenal/patologia , Adenoma Adrenocortical/metabolismo , Adenoma Adrenocortical/patologia , Animais , Proteínas de Ligação ao Cálcio/biossíntese , Masculino , Chaperonas Moleculares/biossíntese , RNA Neoplásico/genética , Ratos , Ratos Endogâmicos Dahl , Testículo , Regulação para Cima
6.
Acta Chir Belg ; 120(1): 23-29, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30499377

RESUMO

Background: To present basic demographic and clinical characteristics of patients with adrenocortical carcinoma (ACC), to determine the overall survival rate and to analyze the results of immunohistochemical staining and its correlation with the length of survival.Material and methods: The study was conducted during the period between 1996 and 2010 and included 30 patients with ACC. Immunohistochemical staining (MMP9, melan A, inhibin, caltretinin, D2-40, synaptophysin and Ki-67) was performed.Results: ACC was diagnosed in 19 females and 11 men (1.7:1). The average age was 50.1 years. The median tumor size was 10 cm, the median weight 400 g. Majority of subjects had positive immunohistochemical staining for the markers of interest. Patients with any negative staining had shorter cancer-specific survival than ones with positive staining. According to the log-rank test results as well as according to the results of the univariate Cox analysis, negative staining for inhibin, D2-40 and synaptophysin and Ki-67 expression ≥7% were associated with poorer prognosis.Conclusions: The results of our study suggest that the absence of staining for some immunohistochemical markers and increased expression of Ki-67 are associated with a poorer prognosis and shorter survival of patients with ACC. Immunohistochemical markers may serve as a prognostic factor for ACC.


Assuntos
Neoplasias do Córtex Suprarrenal/metabolismo , Neoplasias do Córtex Suprarrenal/mortalidade , Carcinoma Adrenocortical/metabolismo , Carcinoma Adrenocortical/mortalidade , Neoplasias do Córtex Suprarrenal/cirurgia , Carcinoma Adrenocortical/cirurgia , Adulto , Idoso , Anticorpos Monoclonais Murinos/metabolismo , Biomarcadores Tumorais/metabolismo , Feminino , Humanos , Inibinas/metabolismo , Antígeno Ki-67/metabolismo , Antígeno MART-1/metabolismo , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Sinaptofisina/metabolismo , Adulto Jovem
7.
Mol Cell Endocrinol ; 500: 110636, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31678420

RESUMO

Adrenocortical tumors (ACTs) frequently cause steroid excess and present cell-cycle dysregulation. cAMP/PKA signaling is involved in steroid synthesis and play a role in cell-cycle regulation. We investigated, by cell synchronization in the different phases of the cell-cycle, the control of steroidogenesis and the contribution of PKA in adrenocortical cells (H295R and culture of primary pigmented nodular adrenocortical disease cells). Cells showed increased steroidogenesis and a maximal PKA activity at G2 phase, and a reduction at G1 phase. PRKACA overexpression, or cAMP stimulation, enhanced PKA activity and induced steroidogenesis in all synchronized groups but is not sufficient to drive cell-cycle progression. PRKAR1A inactivation enhanced PKA activity and induced STAR gene expression, only in cells in G1, and triggered cell-cycle progression in all groups. These findings provide evidence for a tight association between steroidogenesis and cell-cycle in ACTs. Moreover, PRKAR1A is essential for mediating the function of PKA activity on both steroidogenesis and cell-cycle progression in adrenocortical cells.


Assuntos
Neoplasias do Córtex Suprarrenal/metabolismo , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/genética , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/genética , Esteroides/metabolismo , Neoplasias do Córtex Suprarrenal/genética , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Técnicas de Cocultura , AMP Cíclico/metabolismo , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/metabolismo , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/metabolismo , Humanos , Fosfoproteínas/genética , Transdução de Sinais
8.
BMC Cancer ; 19(1): 1165, 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31783819

RESUMO

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare malignant endocrine tumour. Due to a high tumour recurrence rate, the post-operative overall survival (OS) and disease-free survival (DFS) of ACCs is limited. Our research aims to identify the role of the epithelial-mesenchymal transition (EMT) related genes FSCN1 and FOXM1 in the tumour microenvironment and assess their prognostic value in ACCs. METHODS: Clinical and specimen data from 130 adrenocortical carcinoma (ACC) patients was acquired from the Cancer Genome Atlas (TCGA) database (n = 79) and a West China Hospital (WCH) cohort (n = 51). In the WCH cohort, archived formalin-fixed paraffin embedded (FFPE) samples were collected for immunohistochemical analysis. The correlation between the EMT genes and the tumour microenvironment status was estimated based on the Tumour Immune Estimation Resource (TIMER) algorithm. Kaplan-Meier analysis, followed by univariate and multivariate regression analyses, were performed to identify the prognostic association of FSCN1 and FOXM1. RESULTS: FSCN1 and FOXM1 were over-expressed in ACC tissue when compared with adrenocortical adenoma and normal adrenal tissue. Over-expression of FSCN1 or FOXM1 was associated with the tumour microenvironment and immune signatures in ACCs. Patients with higher expression of FSCN1 or FOXM1 were more likely to have worse prognoses. The prognostic effects were further verified in both early (stage I/II) and advanced (stage III/IV) ACCs. Furthermore, FSCN1 and FOXM1 appeared as independent prognostic factors in ACC. CONCLUSIONS: These results show that FSCN1 and FOXM1 are independent prognostic factors in ACCs and over-expression of FSCN1 or FOXM1 indicates a worse prognosis.


Assuntos
Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/patologia , Proteínas de Transporte/metabolismo , Proteína Forkhead Box M1/metabolismo , Proteínas dos Microfilamentos/metabolismo , Adolescente , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/imunologia , Neoplasias do Córtex Suprarrenal/metabolismo , Carcinoma Adrenocortical/genética , Carcinoma Adrenocortical/imunologia , Carcinoma Adrenocortical/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Criança , Pré-Escolar , Transição Epitelial-Mesenquimal/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Regulação para Cima , Adulto Jovem
9.
Med Sci Monit ; 25: 8326-8334, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31689287

RESUMO

BACKGROUND This study aimed to explore the transcript preference of PTK7 in adrenocortical cancer (ACC), the prognostic value, and the potential underlying genetic alterations. MATERIAL AND METHODS Data from the Cancer Genome Atlas-Adrenocortical Cancer (TCGA-ACC) and the Genotype-Tissue Expression (GTEx)-normal adrenal gland were used for analysis. RESULTS A non-canonical alternative transcript, ENST00000489707.5, which only encodes an extracellular immunoglobulin (Ig)-like domain and an intracellular kinase domain, is the dominant isoform of PTK7 in both ACC and normal adrenal gland. Its expression percentage was significantly higher in ACC than in normal adrenal gland. ACC tissues showed preferred expression of this transcript compared with other cancers with known PTK7 expression. Prognostic analysis showed that ENST00000489707.5 had independent prognostic value in progression-free survival (PFS) (HR: 1.227, 95%CI: 1.077-1.398, p=0.002) and disease-specific survival (DSS) (HR: 1.419, 95%CI: 1.154-1.745, p=0.001) after adjustment of other risk factors. cg20819617 methylation was negatively correlated with both PTK7 and ENST00000489707.5 expression. CONCLUSIONS ENST00000489707.5 is a preferred alternative splicing product of PTK7, with a significantly increased proportion in ACC compared with other cancers. Its expression shows potential prognostic value in terms of PFS and DSS in ACC patients. The methylation status of cg20819617 might play a critical role in modulating PTK7 transcription and ENST00000489707.5 expression.


Assuntos
Neoplasias do Córtex Suprarrenal/genética , Moléculas de Adesão Celular/genética , Receptores Proteína Tirosina Quinases/genética , Neoplasias do Córtex Suprarrenal/metabolismo , Adulto , Processamento Alternativo/genética , Biomarcadores Tumorais/genética , Moléculas de Adesão Celular/metabolismo , Metilação de DNA/genética , Bases de Dados Genéticas , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Isoformas de Proteínas/genética , Receptores Proteína Tirosina Quinases/metabolismo
10.
Proc Natl Acad Sci U S A ; 116(44): 22269-22274, 2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31611400

RESUMO

Adrenocortical carcinomas (ACCs) are rare and highly malignant cancers associated with poor survival of patients. Currently, mitotane, a nonspecific derivative of the pesticide DDT (1,1-(dichlorobiphenyl)-2,2-dichloroethane), is used as the standard treatment, but its mechanism of action in ACCs remains elusive. Here we demonstrate that the human ACC NCI-H295R cell line is remarkably sensitive to induction of ferroptosis, while mitotane does not induce this iron-dependent mode of regulated necrosis. Supplementation with insulin, transferrin, and selenium (ITS) is commonly used to keep NCI-H295R cells in cell culture. We show that this supplementation prevents spontaneous ferroptosis, especially when it contains polyunsaturated fatty acids (PUFAs), such as linoleic acid. Inhibitors of apoptosis (zVAD, emricasan) do not prevent the mitotane-induced cell death but morphologically prevent membrane blebbing. The expression of glutathione peroxidase 4 (GPX4) in H295R cells, however, is significantly higher when compared to HT1080 fibrosarcoma cells, suggesting a role for ferroptosis. Direct inhibition of GPX4 in H295R cells led to high necrotic populations compared to control, while cotreatment with ferrostatin-1 (Fer-1) completely reverted ferroptosis. Interestingly, the analysis of public databases revealed that several key players of the ferroptosis pathway are hypermethylated and/or mutated in human ACCs. Finally, we also detected that growth hormone-releasing hormone (GHRH) antagonists, such as MIA602, kill H295R cells in a nonapoptotic manner. In summary, we found elevated expression of GPX4 and higher sensitivity to ferroptosis in ACCs. We hypothesize that instead of treatment with mitotane, human adrenocortical carcinomas may be much more sensitive to induction of ferroptosis.


Assuntos
Neoplasias do Córtex Suprarrenal/metabolismo , Carcinoma Adrenocortical/metabolismo , Ferroptose/efeitos dos fármacos , Células 3T3 , Animais , Apoptose/efeitos dos fármacos , Células HEK293 , Células HT29 , Humanos , Insulina/metabolismo , Ferro/metabolismo , Ácido Linoleico/metabolismo , Camundongos , Mitotano/toxicidade , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Selênio/metabolismo , Sermorelina/análogos & derivados , Sermorelina/farmacologia , Transferrina/metabolismo
11.
BMJ Case Rep ; 12(9)2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31492730

RESUMO

A 46-year-old woman presented with hypertension and renal disease. Investigations showed severe hypercalcaemia due to primary hyperparathyroidism. Imaging demonstrated renal calculi and an incidental left adrenal lesion. Additional biochemistry confirmed adrenocorticotropic hormone-independent hypercortisolism. Ultrasound and sestamibi scan found an enlarged right-sided parathyroid gland and a suspicious right thyroid nodule, biopsy of which suggested papillary carcinoma. The right parathyroid mass, right thyroid lobe and right central compartment tissue along with a segment of the right recurrent laryngeal nerve was resected en-bloc Completion thyroidectomy and left adrenalectomy were performed 6 months later. Histology showed parathyroid cancer, multifocal papillary thyroid cancer and adrenal clear cell cortical adenoma. Genetic tests were normal. There was no evidence of recurrence at 12 months follow-up. Parathyroid cancer should be suspected in the presence of significant hypercalcaemia, very high parathyroid hormone and end organ damage. Suspicious thyroid nodules on imaging should be appropriately investigated.


Assuntos
Neoplasias do Córtex Suprarrenal/diagnóstico por imagem , Adenoma Adrenocortical/diagnóstico por imagem , Carcinoma/diagnóstico por imagem , Neoplasias Primárias Múltiplas/diagnóstico por imagem , Neoplasias das Paratireoides/diagnóstico por imagem , Câncer Papilífero da Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias do Córtex Suprarrenal/metabolismo , Neoplasias do Córtex Suprarrenal/cirurgia , Adenoma Adrenocortical/metabolismo , Adenoma Adrenocortical/cirurgia , Carcinoma/metabolismo , Carcinoma/cirurgia , Síndrome de Cushing/metabolismo , Feminino , Humanos , Hiperparatireoidismo Primário/diagnóstico , Hiperparatireoidismo Primário/metabolismo , Microscopia Acústica , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/metabolismo , Neoplasias Primárias Múltiplas/cirurgia , Neoplasias das Paratireoides/metabolismo , Neoplasias das Paratireoides/cirurgia , Cintilografia , Compostos Radiofarmacêuticos , Tecnécio Tc 99m Sestamibi , Câncer Papilífero da Tireoide/metabolismo , Câncer Papilífero da Tireoide/cirurgia , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/cirurgia , Tomografia Computadorizada por Raios X
12.
Front Horm Res ; 53: 92-99, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31499503

RESUMO

Androgen-secreting tumors are a rare cause of hyperandrogenism of adrenal origin. Although these tumors are identified in less than 2% of patients, the prevalence of adrenocortical carcinomas is relevant (2/3 of the cases). Those tumors are associated with simultaneous elevation of several androgens, mainly androstenedione, DHEAS, and testosterone, in more than half of the patients, as measured either by immunoassay or mass spectrometry. Despite the recent advances on the pathogenesis of adrenocortical tumors, to date no driver molecular event have been identified in those tumors. This chapter provides a comprehensive review of all studies published in the last 20 years on androgen-secreting tumors, with focus on epidemiology, clinical presentation, and hormonal profile.


Assuntos
Neoplasias do Córtex Suprarrenal/metabolismo , Androgênios/metabolismo , Hiperandrogenismo/metabolismo , Neoplasias do Córtex Suprarrenal/epidemiologia , Neoplasias do Córtex Suprarrenal/patologia , Neoplasias do Córtex Suprarrenal/fisiopatologia , Humanos
13.
Drug Des Devel Ther ; 13: 2787-2798, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496655

RESUMO

Objective: Thapsigargin (TG) is a natural product that exists in most parts of the plant Thapsia garganica L. and possesses potential anticancer activities against variety tumor cell lines. TG induces endoplasmic reticulum (ER) stress and apoptosis by inhibiting cancer growth. However, the antineoplastic effect of TG in human adrenocortical carcinoma (ACC) cells is still unknown. Methods: In this study, two human ACC cell lines including SW-13 and NCI-H295R were employed to explore the potential role of TG in ACC. A mouse xenograft model of SW-13 cells was established to verify the role of TG in vivo. The cell viability was tested using Cell Counting Kit-8 and Transwell assays. Flow cytometry and Hoechst 33,258 staining were employed to analyze cell apoptosis. RT-qPCR and Western blot (WB) were performed to explore the underlying mechanism of TG-induced apoptosis in ACC cells. Results: The results indicated that TG dose-dependently inhibited proliferation, migration and invasion in human ACC cells. TG significantly increased the mitochondrial rate of apoptosis and ER stress activity in ACC cells and suppressed ACC xenograft growth in vivo. In addition, the expression of Jun N-terminal kinase (JNK) signaling-related genes and proteins was upregulated by the treatment with TG. Conclusion: Our findings suggest that TG inhibits the viability of ACC cells by inducing apoptosis through the activation of JNK signaling. Thus, TG is expected to be a potential candidate for the treatment of ACC.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Tapsigargina/farmacologia , Neoplasias do Córtex Suprarrenal/metabolismo , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/metabolismo , Carcinoma Adrenocortical/patologia , Animais , Antineoplásicos Fitogênicos/química , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Thapsia/química , Tapsigargina/química , Células Tumorais Cultivadas
14.
Clin Nucl Med ; 44(12): 943-948, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31490313

RESUMO

PURPOSE: The purposes of this study were to investigate the correlation between unenhanced CT attenuation values and F-FDG uptake in adrenal adenomas, and to clarify the mechanism of FDG uptake in adrenal adenomas based on immunohistochemical findings. MATERIALS AND METHODS: In 57 adrenal adenomas, the correlation between SUVmax on F-FDG PET and unenhanced CT attenuation was retrospectively investigated. In the 11 surgically resected nodules, the clear cell ratio (CCR) and expression levels of glucose transporters (GLUTs) 1 to 4 were pathologically evaluated. The GLUT expression levels were scored at 0 to 3 points for each transporter, and the sum of these expression levels was defined as the GLUT score. The relationships between CCR and either the CT attenuation number or SUVmax, and between the GLUT score and each of the CT attenutation value, SUVmax, or CCR were evaluated. RESULTS: There was a significant positive correlation between SUVmax and the CT attenuation value for the group of 57 adenomas (R = 0.44, P = 0.0007). For the 11 surgically resected cases, there was a nonsignificant trend of negative correlation between SUVmax and CCR (R = 0.57, P = 0.06). There was a significant positive correlation between GLUT score and CT attenuation value (R = 0.68, P = 0.02), and a significant negative correlation between GLUT score and CCR (R = 0.60, P = 0.003). CONCLUSIONS: Adrenal adenomas composed of many compact cells or having high attenuation on unenhanced CT showed high FDG uptake. FDG uptake of adrenal adenomas may depend on the constituent cells.


Assuntos
Neoplasias do Córtex Suprarrenal/diagnóstico por imagem , Neoplasias do Córtex Suprarrenal/metabolismo , Adenoma Adrenocortical/diagnóstico por imagem , Adenoma Adrenocortical/metabolismo , Fluordesoxiglucose F18/metabolismo , Tomografia Computadorizada por Raios X , Neoplasias do Córtex Suprarrenal/patologia , Adenoma Adrenocortical/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Transporte Biológico , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
15.
BMC Genomics ; 20(1): 655, 2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31419939

RESUMO

BACKGROUND: Adrenocortical adenomas (ACAs) can lead to the autonomous secretion of aldosterone responsible for primary aldosteronism (PA), which is the most common form of secondary arterial hypertension. However, the authentic fundamental mechanisms underlying ACAs remain unclear. OBJECTIVE: Isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomics and bioinformatics analyses from etiological studies of ACAs were performed to screen the differentially expressed proteins (DEPs) and investigate the relevant mechanisms of their occurrence and development. Results could help determine therapeutic targets of clinical significance. METHODS: In the present study, iTRAQ-based proteomics was applied to analyze ACA tissue samples from normal adrenal cortex tissues adjacent to the tumor. Using proteins extracted from a panel of four pairs of ACA samples, we identified some upregulated proteins and other downregulated proteins in all four pairs of ACA samples compared with adjacent normal tissue. Subsequently, we predicted protein-protein interaction networks of three DEPs to determine the authentic functional factors in ACA. RESULTS: A total of 753 DEPs were identified, including 347 upregulated and 406 downregulated proteins. The expression of three upregulated proteins (E2F3, KRT6A, and ALDH1A2) was validated by Western blot in 24 ACA samples. Our data suggested that some DEPs might be important hallmarks during the development of ACA. CONCLUSIONS: This study is the first proteomic research to investigate alterations in protein levels and affected pathways in ACA using the iTRAQ technique. Thus, this study not only provides a comprehensive dataset on overall protein changes but also sheds light on its potential molecular mechanism in human ACAs.


Assuntos
Neoplasias do Córtex Suprarrenal/metabolismo , Adenoma Adrenocortical/metabolismo , Neoplasias do Córtex Suprarrenal/etnologia , Aldeído Desidrogenase 1/metabolismo , Regulação para Baixo , Fator de Transcrição E2F3/metabolismo , Feminino , Ontologia Genética , Humanos , Queratina-6/metabolismo , Masculino , Mapas de Interação de Proteínas , Proteômica/métodos , Retinal Desidrogenase/metabolismo , Regulação para Cima
16.
J Trace Elem Med Biol ; 56: 52-59, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31442954

RESUMO

INTRODUCTION: Iron metabolism is tightly controlled in human cells. Dysregulation of iron metabolism-related genes has been characterized as a promising prognostic biomarker in cancers. However, the expression patterns and prognostic roles of iron metabolism-related genes remain unknown in adrenocortical carcinoma (ACC). OBJECTIVES: The primary objective of this study was to explore the expression patterns and prognostic roles of iron metabolism-related genes in ACC using publicly available datasets. METHODS: In the present study, we compared the expression patterns of 36 iron metabolism-related genes between ACC tumors (n = 77) and normal adrenal tissues (n = 128) based on The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) data. The associations between clinical variables (including survival rate and pathological stage) and expression levels of iron mentalism-related genes were further explored. All the bioinformatics analyses were performed using the GEPIA or the Metascape tool. RESULTS: Twelve iron metabolism-related genes were differentially expressed between ACC tumors and normal controls. Among them, reduced expression levels of ferroportin1 (FPN1) and ceruloplasmin (CP) were significantly correlated with poor survival of ACC patients. Specially, the expression levels of FPN1 were negatively correlated with the pathological stages of ACC. A pan-cancer analysis characterized the reduced expression of FPN1 and CP as an ACC-specific signature among 33 types of cancers. Functional enrichment analysis suggested that both FPN1 and CP might be implicated in several immune processes. CONCLUSION: Reduced expression of FPN1 and CP was identified as a potential signature for poor prognosis of ACC in this study. Mechanisms underlying the prognostic value of FPN1 or CP in ACC deserve further experimental investigation.


Assuntos
Neoplasias do Córtex Suprarrenal/diagnóstico , Neoplasias do Córtex Suprarrenal/metabolismo , Carcinoma Adrenocortical/diagnóstico , Carcinoma Adrenocortical/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Ceruloplasmina/metabolismo , Neoplasias do Córtex Suprarrenal/genética , Carcinoma Adrenocortical/genética , Estudos de Casos e Controles , Proteínas de Transporte de Cátions/genética , Ceruloplasmina/genética , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Ferro/metabolismo , Prognóstico , Transdução de Sinais/genética , Análise de Sobrevida , Microambiente Tumoral/genética
18.
Hormones (Athens) ; 18(3): 307-313, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31399957

RESUMO

AIMS AND OBJECTIVES: Adrenal adenomas are usually non-functioning, but can secrete aldosterone or cortisol. It has recently been suggested that many more adenomas than previously thought secrete more than one hormone. This has important implications for their clinical management. Our aim was to determine the frequency of cortisol co-secretion in primary hyperaldosteronism at our institution and investigate the difference in metabolic profiles and clinical outcomes between co-secreting and non-co-secreting patients. DESIGN AND PATIENTS: A retrospective study of 25 patients with primary hyperaldosteronism who also underwent formal dexamethasone suppression tests to determine cortisol co-secretion. MEASUREMENTS: Post-dexamethasone suppression test cortisol, serum ALT, total cholesterol, HDL-cholesterol, LDL-cholesterol, HbA1C (were recorded) and mean arterial pressure are reported in this cohort of patients with primary hyperaldosteronism. RESULTS: Four out of 25 patients with primary hyperaldosteronism failed dexamethasone suppression tests. This suggests a frequency of co-secretion ranging between 4 and 16%. No significant difference was found in serum ALT, total cholesterol, serum HDL-cholesterol, LDL-cholesterol and mean arterial blood pressure at presentation between co-secretors and non-co-secretors. CONCLUSION: A frequency range of 4-16% suggests that a significant proportion of patients with primary hyperaldosteronism co-secrete cortisol. Co-secretors did not have a worse metabolic profile than non-secretors. The impact of co-secretion on metabolic profile and surgical management remains unclear and warrants further study.


Assuntos
Neoplasias do Córtex Suprarrenal/metabolismo , Adenoma Adrenocortical/metabolismo , Aldosterona/metabolismo , Hidrocortisona/metabolismo , Hiperaldosteronismo/metabolismo , Neoplasias do Córtex Suprarrenal/complicações , Neoplasias do Córtex Suprarrenal/diagnóstico , Adenoma Adrenocortical/complicações , Adenoma Adrenocortical/diagnóstico , Adulto , Dexametasona/farmacologia , Técnicas de Diagnóstico Endócrino , Feminino , Humanos , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/etiologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Via Secretória
19.
Vet Comp Oncol ; 17(4): 545-552, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31301217

RESUMO

Hypercortisolism is caused by a cortisol-secreting adrenocortical tumour (ACT) in approximately 15%-20% of cases in dogs. Little is known about which molecular markers are associated with malignant behaviour of canine ACTs. The objective of this study was to identify molecular markers of prognosis, which could be useful to refine prognostic prediction and to identify potential treatment targets. Cortisol-secreting ACTs were included from 40 dogs, of which follow-up information was available. The ACTs were classified as low risk of recurrence tumours (LRT; n = 14) or moderate-high risk of recurrence tumours (MHRT; n = 26), based on the novel histopathological Utrecht score. Normal adrenals (NAs) were included from 11 healthy dogs as reference material. The mRNA expression of 14 candidate genes was analysed in the 40 ACTs and in 11 NAs with quantitative RT-PCR. The genes' expression levels were statistically compared between NAs, LRTs and MHRTs. Univariate and multivariate analyses were performed to determine the association of the genes' expression levels with survival. Seven genes were differentially expressed between NAs and ACTs, of which pituitary tumour-transforming gene-1 (PTTG1) and topoisomerase II alpha (TOP2A) were also differentially expressed between LRTs and MHRTs. In survival analyses, high expression levels of Steroidogenic factor-1 (SF-1), PTTG1 and TOP2A were significantly associated with poor survival. In conclusion, we have identified several genes that are part of the molecular signature of malignancy in canine ACTs. These findings can be used to refine prognostic prediction, but also offer insights for future studies on druggable targets.


Assuntos
Neoplasias do Córtex Suprarrenal/veterinária , Glândulas Suprarrenais/metabolismo , Biomarcadores Tumorais/sangue , Doenças do Cão/sangue , Hidrocortisona/metabolismo , Neoplasias do Córtex Suprarrenal/sangue , Neoplasias do Córtex Suprarrenal/metabolismo , Neoplasias do Córtex Suprarrenal/patologia , Animais , Doenças do Cão/patologia , Cães , Regulação da Expressão Gênica/fisiologia , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
20.
J Steroid Biochem Mol Biol ; 193: 105434, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31351131

RESUMO

Intracellular calcium (Ca) levels play pivotal roles in aldosterone biosynthesis. Several somatic mutations of ion channels associated with aldosterone over-production were reported to result in over-inflow of Ca ion. Recently, the main regulators of extracellular Ca including VDR, CaSR and PTH1R were also reported to regulate steroidogenesis including aldosterone production. Therefore, not only intracellular but also extracellular Ca levels could regulate aldosterone biosynthesis. In addition, primary aldosteronism (PA) is clinically associated with not only more frequent cardiovascular events but also secondary metabolic disorders including abnormal calcium metabolism, osteoporosis and others. However, the details of Ca metabolic abnormalities associated with, including the potential correlation between those abnormalities and aldosterone overproduction, have remained virtually unknown. Therefore, in this study, we first immunolocalized Ca metabolism-related receptors (CaSR, VDR and PTH1R) in normal adrenal glands (NAs), aldosterone-producing adenomas (APAs) and cortisol-producing adenoma (CPA). We then compared the findings with clinicopathological parameters of these patients and the patterns of KCNJ5 somatic mutation of the tumors among APA patients. In vitro study was also performed to further explore the potential effects of extracellular Ca, PTH, Vitamin D and ionophore on aldosterone production. Ca metabolism-related receptors were predominantly localized in aldosterone-producing cells (ZG and APA) in both immunohistochemistry and qRT-PCR analysis. CYP11B2 mRNA was significantly increased by CaCl2 treatment and further by adding ionophore. All the key enzymes related to aldosterone and cortisol biosynthesis including CYP11B2, CYP17A1 and CYP11B1 were upregulated by PTH treatment in this model and PTH could serve as a co-stimulator of ANG II to increase CYP11B2 expression. VDR mRNA levels were positively correlated with those of CYP11B2, CYP17A1 and CYP11B1 in APA tumor tissues and significantly higher in KCNJ5 mutated APAs than wild type. CYP11B1 levels were also significantly increased by VitD treatment. PTH1R mRNA levels were positively correlated with those of CYP17A1 and CYP11B1, both involved in cortisol production. In addition, the status of VDR was correlated with TRACP-5b levels, and that of PTH1R with serum Ca levels as well as urinary Ca excretion, respectively. Results of our present study did firstly demonstrate that aldosterone-producing cells were more sensitive to the fluctuations of extracellular Ca levels and Ca metabolism could directly influence steroidogenesis, especially "neoplastic" co-secretion of aldosterone and cortisol in APA patients.


Assuntos
Glândulas Suprarrenais/metabolismo , Aldosterona/metabolismo , Cálcio/metabolismo , Hiperaldosteronismo/metabolismo , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/metabolismo , Adenoma Adrenocortical/genética , Adenoma Adrenocortical/metabolismo , Adulto , Idoso , Linhagem Celular Tumoral , Sistema Enzimático do Citocromo P-450/genética , Feminino , Humanos , Hiperaldosteronismo/genética , Masculino , Pessoa de Meia-Idade , Receptor Tipo 1 de Hormônio Paratireóideo/metabolismo , Receptores de Calcitriol/metabolismo , Receptores de Detecção de Cálcio/metabolismo , Adulto Jovem
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