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1.
Life Sci ; 260: 118416, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32926922

RESUMO

BACKGROUND: Non-functioning pituitary adenomas (NFPAs) are common pituitary tumors, and surgery is generally the only treatment option. Few attempts have been made to explore target molecules for the development of NFPA pharmacological treatments. METHOD: We quantitatively assessed the expression profiles of estrogen receptor (ER) transcripts and proteins in NFPA samples, using reverse transcription-digital polymerase chain reaction (RT-dPCR) and immunohistochemistry, and further investigated the correlations between the expression levels of ER and those of downstream responsive genes. All patients had undergone surgery at the same high-volume hospital. A total of 20 patients with NFPAs were included. All patients were new-onset, and none were diagnosed with intratumoral hemorrhages or cysts. RESULTS: NFPA samples exhibited a bimodal ESR1 expression pattern and were categorized into significantly different high- and low-ESR1 expression level groups (P < 0.05). In contrast, expression levels of ESR1 variants and ESR2 could barely be detected. Similar results were obtained through the immunohistochemical staining of NFPAs, using well-validated antibodies against ERs. The expression levels of ESR1 positively correlated with those of GREB1, an estrogen-responsive gene [correlation coefficient (r) = 0.623, P = 0.003]. CONCLUSIONS: ESR1 expression levels in NFPAs exhibited a bimodal pattern and were positively correlated with GREB1 expression levels. The accurate assessment of ER expression levels may further advance future NFPA-related research.


Assuntos
Adenoma/patologia , Biomarcadores Tumorais/metabolismo , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Hipofisárias/patologia , Adenoma/genética , Adenoma/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/genética , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/metabolismo , Prognóstico , Reação em Cadeia da Polimerase Via Transcriptase Reversa
2.
Eur J Endocrinol ; 183(4): 369-379, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32621582

RESUMO

Background: The '3PAs' syndrome, associating pituitary adenoma (PA) and pheochromocytoma/paraganglioma (PPGL), is sometimes associated with mutations in PPGL-predisposing genes, such as SDHx or MAX. In '3PAs' syndrome, PAs can occur before PPGL, suggesting a new gateway into SDHx/MAX-related diseases. Objective: To determine the SDHx/MAX mutation prevalence in patients with isolated PAs and characterize PAs of patients with SDHx/MAX mutations. Design: Genes involved in PAs (AIP/MEN1/CDKN1B) or PPGLs (SDHx/MAX) were sequenced in patients with isolated PAs. We then conducted a review of cases of PA in the setting of '3PAs' syndrome. Results: A total of 263 patients were recruited. Seven (likely) pathogenic variants were found in AIP, two in MEN1, two in SDHA, and one in SDHC. The prevalence of SDHx mutations reached 1.1% (3/263). Of 31 reported patients with PAs harboring SDHx/MAX mutations (28 published cases and 3 cases reported here), 6/31 (19%) developed PA before PPGL and 8/31 (26%) had isolated PA. The age of onset was later than in patients with AIP/MEN1 mutations. PAs were mainly macroprolactinomas and showed intracytoplasmic vacuoles seen on histopathology. Conclusions: We discovered SDHx mutations in patients bearing PA who had no familial or personal history of PPGL. However, the question of incidental association remains unresolved and data to determine the benefit of SDHx/MAX screening in these patients are lacking. We recommend that patients with isolated PA should be carefully examined for a family history of PPGLs. A family history of PPGL, as well as the presence of intracytoplasmic vacuoles in PA, requires SDHx/MAX genetic testing of patients.


Assuntos
Adenoma/genética , Mutação em Linhagem Germinativa , Neoplasias Hipofisárias/genética , Succinato Desidrogenase/genética , Adenoma/epidemiologia , Adenoma/patologia , Adolescente , Neoplasias das Glândulas Suprarrenais/epidemiologia , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/patologia , Adulto , Idade de Início , Idoso , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Criança , Análise Mutacional de DNA/métodos , Feminino , França/epidemiologia , Predisposição Genética para Doença , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Isoenzimas/genética , Masculino , Pessoa de Meia-Idade , Paraganglioma/epidemiologia , Paraganglioma/genética , Paraganglioma/patologia , Feocromocitoma/epidemiologia , Feocromocitoma/genética , Feocromocitoma/patologia , Neoplasias Hipofisárias/epidemiologia , Neoplasias Hipofisárias/patologia , Prolactinoma/epidemiologia , Prolactinoma/genética , Prolactinoma/patologia , Subunidades Proteicas/genética , Estudos Retrospectivos , Adulto Jovem
3.
J Endocrinol ; 244(2): 415-429, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-32395971

RESUMO

Among all the hormone-secreting pituitary tumours, prolactinomas are the most frequently found in the clinic. Since dopamine is the primary inhibitor of lactotroph function, dopamine agonists represent the first-line therapy. However, a subset of patients exhibits resistance to these drugs, and therefore, alternative treatments are desired. As activins inhibit prolactin gene expression through the inhibition of Pit-1 involving the p38MAPK pathway, in the present work, we studied the local activin system as an alternative inhibitory system for lactotroph hyperplasia treatment. We used two different mouse models of prolactinoma: transgenic mice with overexpression of the human chorionic gonadotropin ß-subunit (hCGß) and mice lacking dopamine receptor type 2. In both models, females, but not males, develop lactotroph hyperplasia from the fourth month of life. We found reduced expression of pituitary activin subunits and activin receptors in hyperplastic pituitaries from both models compared with wild-type counterparts. Consequently, hyperplastic pituitaries presented a reduced activin-inhibitory action on prolactin secretion. Additionally, while female wild-type lactotrophs presented high levels of phospho-p38MAPK, it was lost in prolactinomas, concomitant with decreased activin expression, increased Pit-1 expression and tumour development. In contrast, male pituitaries express higher mRNA levels of activin subunits ßA and ßB, which would suggest a stronger activin inhibitory function on lactotrophs, protecting this sex from tumour development, despite genotype. The present results highlight the importance of the activin inhibitory action on lactotroph function and place the local activin system as a new target for the treatment of dopamine agonist-resistant prolactinomas.


Assuntos
Ativinas/metabolismo , Lactotrofos/metabolismo , Neoplasias Hipofisárias/genética , Prolactinoma/genética , Animais , Agonistas de Dopamina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Genótipo , Sistema de Sinalização das MAP Quinases/genética , Masculino , Camundongos , Camundongos Transgênicos , Hipófise/metabolismo , Neoplasias Hipofisárias/complicações , Neoplasias Hipofisárias/tratamento farmacológico , Prolactinoma/complicações , Prolactinoma/tratamento farmacológico , RNA Mensageiro/metabolismo , Fatores Sexuais , Fator de Transcrição Pit-1/metabolismo
4.
Best Pract Res Clin Endocrinol Metab ; 34(2): 101418, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32414619

RESUMO

Cushing syndrome (CS) describes the signs and symptoms caused by exogenous or endogenous hypercortisolemia. Endogenous CS is caused by either ACTH-dependent sources (pituitary or ectopic) or ACTH-independent (adrenal) hypercortisolemia. Several genes are currently known to contribute to the pathogenesis of CS. Germline gene defects, such as MEN1, AIP, PRKAR1A and others, often present in patients with pituitary or adrenal involvement as part of a genetic syndrome. Somatic defects in genes, such as USP8, TP53, and others, are also involved in the development of pituitary or adrenal tumors in a large percentage of patients with CS, and give insight in pathways involved in pituitary or adrenal tumorigenesis.


Assuntos
Síndrome de Cushing/genética , Análise Mutacional de DNA , Neoplasias das Glândulas Suprarrenais/complicações , Neoplasias das Glândulas Suprarrenais/epidemiologia , Neoplasias das Glândulas Suprarrenais/genética , Carcinogênese/genética , Carcinogênese/patologia , Síndrome de Cushing/epidemiologia , Análise Mutacional de DNA/métodos , Análise Mutacional de DNA/tendências , Estudos de Associação Genética/métodos , Estudos de Associação Genética/tendências , Predisposição Genética para Doença , Mutação em Linhagem Germinativa/fisiologia , Humanos , Neoplasias Hipofisárias/complicações , Neoplasias Hipofisárias/epidemiologia , Neoplasias Hipofisárias/genética , Transdução de Sinais/genética
6.
J Clin Neurosci ; 78: 420-422, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32336638

RESUMO

Gigantism (early-onset acromegaly) is a rare pediatric disorder caused by a growth hormone (GH)-secreting pituitary adenoma. Approximately 50% patients of gigantism have a germline mutation, most commonly an inactivating mutation in the aryl-hydrocarbon interacting receptor protein (AIP) gene on chromosome 11q13.2. We present an 11-year-old male patient with a GH-secreting pituitary macroadenoma who presented with excessive growth spurts, behavioral changes, and frontal headaches. He was successfully treated with an endoscopic endonasal gross total resection and subsequently demonstrated biochemical cure. Whole-exome sequencing showed a heterozygous germline mutation in the AIP gene suggesting pituitary adenoma predisposition. Analysis of the tumor tissue revealed a large-scale deletion on chromosome 11 overlapping with AIP leading to bi-allelic AIP loss. Coincident germline and somatic AIP mutations were likely causal in formation of a GH-secreting adenoma with an aggressive phenotype. This case exemplifies the need for early diagnosis and curative surgery in the management of AIP-mutated pituitary adenomas.


Assuntos
Mutação em Linhagem Germinativa , Gigantismo/etiologia , Adenoma Hipofisário Secretor de Hormônio do Crescimento/complicações , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Hipofisárias/patologia , Criança , Cromossomos Humanos Par 11/genética , Gigantismo/genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/patologia , Adenoma Hipofisário Secretor de Hormônio do Crescimento/cirurgia , Heterozigoto , Humanos , Masculino , Fenótipo , Neoplasias Hipofisárias/genética , Deleção de Sequência
7.
Medicina (B Aires) ; 80(2): 181-184, 2020.
Artigo em Espanhol | MEDLINE | ID: mdl-32282328

RESUMO

Most pituitary adenomas are sporadic, but 3-5% can occur in a family and hereditary context. This is the case of multiple endocrine neoplasia type 1 (MEN1), Carney complex (CNC) and familial isolated pituitary adenomas (FIPA). FIPA is an infrequent condition that occurs in a family context, not associated with MEN type1 or CNC. FIPA kindred can be homogeneous (all adenomas affected in the family having the same tumor phenotype) or heterogeneous (different tumor phenotypes in the affected members). We describe a Congolese family in which two sisters and a cousin were diagnosed with a prolactinoma (homogenous FIPA) at the ages of 29, 32 and 40 years, respectively. The patients presented with macroadenomas at the time of diagnosis, non-invasive tumors and good biological response to cabergoline treatment (maximum dose of 1.5 mg/weekly). Of these two sisters, one went through a pregnancy without complications. Because no MEN1 and CNC clinical and biochemical features were detected during the 12-year follow-up, these genes were not investigated. The genetic analysis of the aryl hydrocarbon receptor interacting protein (AIP) was normal. As nearly 80% of patients with FIPA do not have a mutation in the AIP gene, future studies in these families are required to identify other affected genes involved in their physiopathology.


Assuntos
Adenoma/genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento , Neoplasias Hipofisárias/genética , Adenoma/diagnóstico , Adulto , Feminino , Humanos , Espectroscopia de Ressonância Magnética , Neoplasia Endócrina Múltipla Tipo 1/genética , Mutação , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Neoplasias Hipofisárias/diagnóstico
8.
Oncogene ; 39(16): 3367-3380, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32111982

RESUMO

Overactivation of the cAMP signal transduction pathway plays a central role in the pathogenesis of endocrine tumors. Genetic aberrations leading to increased intracellular cAMP or directly affecting PKA subunit expression have been identified in inherited and sporadic endocrine tumors, but are rare indicating the presence of nongenomic pathological PKA activation. In the present study, we examined the impact of hypoxia on PKA activation using human growth hormone (GH)-secreting pituitary tumors as a model of an endocrine disease displaying PKA-CREB overactivation. We show that hypoxia activates PKA and enhances CREB transcriptional activity and subsequently GH oversecretion. This is due to a previously uncharacterized ability of HIF-1α to suppress the transcription of the PKA regulatory subunit 2B (PRKAR2B) by sequestering Sp1 from the PRKAR2B promoter. The present study reveals a novel mechanism through which the transcription factor HIF-1α transduces environmental signals directly onto PKA activity, without affecting intracellular cAMP concentrations. By identifying a point of interaction between the cellular microenvironment and intracellular enzyme activation, neoplastic, and nonneoplastic diseases involving overactivated PKA pathway may be more efficiently targeted.


Assuntos
Subunidade RIIbeta da Proteína Quinase Dependente de AMP Cíclico/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias Hipofisárias/genética , Ativação Transcricional/genética , Linhagem Celular Tumoral , Subunidade RIIalfa da Proteína Quinase Dependente de AMP Cíclico/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Imunoglobulinas/genética , Fosforilação/genética , Neoplasias Hipofisárias/patologia , Transdução de Sinais/genética , Hipóxia Tumoral/genética
9.
Rev Invest Clin ; 72(1): 8-18, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32132734

RESUMO

The pituitary gland is responsible for the synthesis and secretion of various hormones that play a key role in regulating endocrine function and homeostasis. Pituitary adenomas (PA) are benign epithelial tumors arising from the endocrine cells of the anterior pituitary gland. Clinically relevant PA are relatively common and they occur in 0.1% of the general population. They are mostly benign monoclonal neoplasms that arise from any of the five hormone-secreting cell types of the anterior pituitary gland. PA are categorized as either functioning or non-functioning, depending on whether or not they produce a hormonal hypersecretion syndrome. Both functioning and non-functioning adenomas can produce symptoms or signs resulting from compression of the optic chiasm or invasion of cavernous sinuses. Only 5% of PA occur within the context of hereditary syndromes with reasonably well-defined oncogenic mechanisms. The vast majority of PA are sporadic, and their etiopathogenesis remains largely unknown. Pituitary tumor oncogenesis involves several mechanisms that eventually lead to abnormal cell proliferation and dysregulated hormone production. Among these factors, we found inactivating mutations of tumor suppressor genes, activating mutation of oncogenes and the participation of hormonal signals coming from the hypothalamus, all resulting in cell-cycle regulation abnormalities. In this review, we summarize the clinical and pathophysiological aspects of the different hereditary pituitary tumor syndromes.


Assuntos
Adenoma/patologia , Hipófise/patologia , Neoplasias Hipofisárias/patologia , Adenoma/epidemiologia , Adenoma/genética , Animais , Humanos , Mutação , Neoplasias Hipofisárias/epidemiologia , Neoplasias Hipofisárias/genética , Síndrome
10.
World Neurosurg ; 138: 89-92, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32059964

RESUMO

BACKGROUND: Recent molecular investigations for craniopharyngiomas have investigated possible predictive biologic markers. Growth hormone receptor (GHR) is thought to be involved in tumor aggressiveness, and high expression of GHR is associated with shorter duration of postoperative stable disease. CASE DESCRIPTION: A 27-year-old man with a large suprasellar tumor underwent an inexplicable clinical course. Transsphenoidal surgery achieved gross total removal of the tumor. Histologic diagnosis was adamantinomatous craniopharyngioma, and immunohistochemistry revealed very low GHR expression. He was discharged with multiple hormonal supplements except for growth hormone. Recurrence was detected 18 months later, and removal of the second tumor was performed with coagulation of the superior surface of the remaining pituitary gland. Growth hormone supplementation was started in the postoperative period, and he returned to work. However, a further recurrence was detected. Head magnetic resonance imaging showed almost the same pattern of tumor recurrence as preoperative imaging of the second surgery, and simultaneous removal of the tumor and the normal pituitary gland was performed. Reevaluation of histology revealed no morphologic differences between the first and the third surgical specimens, but immunohistochemical staining for GHR showed diffuse high expression in the third specimen. The difference was thought to reflect the heterogeneity of GHR, and appearance of histologic hot spots greatly affected the postoperative prognosis. CONCLUSIONS: Extensive removal of the possible tumor bed may be necessary for patients requiring growth hormone supplementation even after gross total removal of craniopharyngioma.


Assuntos
Craniofaringioma/genética , Craniofaringioma/cirurgia , Procedimentos Neurocirúrgicos/métodos , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/cirurgia , Receptores da Somatotropina/biossíntese , Receptores da Somatotropina/genética , Adulto , Craniofaringioma/metabolismo , Humanos , Imagem por Ressonância Magnética , Masculino , Recidiva Local de Neoplasia , Planejamento de Assistência ao Paciente , Neoplasias Hipofisárias/metabolismo , Prognóstico , Reoperação , Tomografia Computadorizada por Raios X
11.
J Endocrinol ; 245(1): 101-113, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32027601

RESUMO

Pituitary-directed medical treatment for Cushing's disease (CD) is currently represented by membrane receptor targeting drugs (somatostatin analogs and dopamine agonists). Somatostatin and dopamine receptors are regulated by ß-arrestins, which have been shown to be differentially regulated by glucocorticoids in non-neuroendocrine cells. In this study we investigated the effects of glucocorticoids on ß-arrestin expression in corticotroph tumor cells. First, AtT20 cells, a mouse model of CD, were exposed to dexamethasone (Dex) at different time points and ß-arrestin expression was evaluated at mRNA and protein levels. Futhermore, ß-arrestin mRNA expression was evaluated in 17 human corticotroph adenoma samples and correlated to patients' pre-operative cortisol levels. We observed that Dex treatment induced a time-dependent increase in ß-arrestin 1 mRNA expression and a decrease in ß-arrestin 2. The same modulation pattern was observed at protein level. Dex-mediated modulation of ß-arrestins was abolished by co-treatment with mifepristone, and Dex withdrawal restored ß-arrestin expression to basal levels after 72 h. The evaluation of ß-arrestin mRNA in corticotroph adenomas from CD patients with variable disease activity showed a significant positive correlation between ß-arrestin 1 mRNA and urinary cortisol levels. The effect of glucocorticoids on ß-arrestin levels was confirmed by the analysis of two samples from a single patient, which underwent adenomectomy twice, with different pre-operative cortisol levels. In conclusion, glucocorticoids induce an inverse modulation of the two ß-arrestin isofoms in corticotroph tumor cells. Since ß-arrestins regulate membrane receptor functions, this finding may help to better understand the variable response to pituitary-targeting drugs in patients with Cushing's disease.


Assuntos
Adenoma Hipofisário Secretor de ACT/genética , Adenoma/genética , Glucocorticoides/farmacologia , Neoplasias Hipofisárias/genética , beta-Arrestina 1/genética , beta-Arrestina 2/genética , Adenoma Hipofisário Secretor de ACT/metabolismo , Adenoma Hipofisário Secretor de ACT/patologia , Adenoma/metabolismo , Adenoma/patologia , Adulto , Idoso , Animais , Anti-Inflamatórios/farmacologia , Cabergolina/uso terapêutico , Linhagem Celular Tumoral , Dexametasona/farmacologia , Quimioterapia Combinada , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Cetoconazol/uso terapêutico , Masculino , Camundongos , Pessoa de Meia-Idade , Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Hipersecreção Hipofisária de ACTH/genética , Hipersecreção Hipofisária de ACTH/metabolismo , Hipófise/efeitos dos fármacos , Hipófise/metabolismo , Hipófise/patologia , Neoplasias Hipofisárias/metabolismo , Neoplasias Hipofisárias/patologia , beta-Arrestina 1/metabolismo , beta-Arrestina 2/metabolismo
12.
J Endocrinol ; 245(2): 179-191, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32092035

RESUMO

The molecular mechanisms underlying the capability of pituitary tumours to avoid unregulated cell proliferation are still not well understood. However, the NF-κB transcription factor, which is able to modulate not only cellular senescence but also tumour progression, has emerged as a targeted candidate. This work was focused on the NF-κB role in cellular senescence during the progression of experimental pituitary tumours. Also, the contribution of the signalling pathways in senescence-associated NF-κB activation and the senescence-associated secretory phenotype (SASP) and pro-survival-NF-κB target genes transcription were analysed. A robust NF-κB activation was seen at E20-E40 of tumour development accompanied by a marked SA-ß-Gal co-reactivity in the tumour pituitary parenchyma. The induction of TNFα and IL1-ß as specific SASP-related NF-κB target genes as well as Bcl-2 and Bcl-xl pro-survival genes was shown to be accompanied by increases in the p-p38 MAPK protein levels, starting at the E20 stage and strengthening from 40 to 60 days of tumour growth. It is noteworthy that p-JNK displayed a similar pattern of activation during pituitary tumour development, while p-AKT and p-ERK1/2 were downregulated. By employing a pharmacological strategy to abrogate NF-κB activity, we demonstrated a marked reduction in SA-ß-Gal activity and a slight decrease in Ki67 immunopositive cells after NF-κB blockade. These results suggest a central role for NF-κB in the regulation of the cellular senescence programme, leading to the strikingly benign intrinsic nature of pituitary adenomas.


Assuntos
Senescência Celular/genética , NF-kappa B/fisiologia , Neoplasias Hipofisárias/genética , Transdução de Sinais/genética , Animais , Modelos Animais de Doenças , Regulação da Expressão Gênica , Genes bcl-2/fisiologia , Hipoxantina Fosforribosiltransferase/metabolismo , Interleucina-1beta/metabolismo , Masculino , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismo , Proteína bcl-X/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
13.
Int J Mol Sci ; 21(4)2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32070065

RESUMO

Croton is an extensive flowering plant genus in the spurge family, Euphorbiaceae. Three croton compounds with the common ent-kaurane skeleton have been purified from Croton tonkinensis. METHODS: We examined any modifications of croton components (i.e., croton-01 [ent-18-acetoxy-7α-hydroxykaur-16-en-15-one], croton-02 [ent-7α,14ß-dihydroxykaur-16-en-15-one] and croton-03 [ent-1ß-acetoxy-7α,14ß-dihydroxykaur-16-en-15-one] on either hyperpolarization-activated cation current (Ih) or erg-mediated K+ current identified in pituitary tumor (GH3) cells and in rat insulin-secreting (INS-1) cells via patch-clamp methods. RESULTS: Addition of croton-01, croton-02, or croton-03 effectively and differentially depressed Ih amplitude. Croton-03 (3 µM) shifted the activation curve of Ih to a more negative potential by approximately 11 mV. The voltage-dependent hysteresis of Ih was also diminished by croton-03 administration. Croton-03-induced depression of Ih could not be attenuated by SQ-22536 (10 µM), an inhibitor of adenylate cyclase, but indeed reversed by oxaliplatin (10 µM). The Ih in INS-1 cells was also depressed effectively by croton-03. CONCLUSION: Our study highlights the evidence that these ent-kaurane diterpenoids might conceivably perturb these ionic currents through which they have high influence on the functional activities of endocrine or neuroendocrine cells.


Assuntos
Croton/química , Diterpenos de Caurano/farmacologia , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/antagonistas & inibidores , Neoplasias Hipofisárias/tratamento farmacológico , Adenilil Ciclases/genética , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Diterpenos de Caurano/química , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/química , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/genética , Estrutura Molecular , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/patologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Ratos
14.
BMC Endocr Disord ; 20(1): 18, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31996203

RESUMO

BACKGROUND: Apart from PRKAR1A mutations in a subset of cyclical Cushing's syndrome due to primary pigmented nodular adrenocortical disease, the molecular basis of cyclical Cushing's syndrome has not been investigated. We speculated that cyclical Cushing's syndrome may be due to mutations in the clock genes that govern circadian rhythms, including the hypothalamic-pituitary-adrenal axis. CASE PRESENTATION: A 47-year-old man presented with mass effects from a sellar lesion. He was ultimately diagnosed with cyclical Cushing's disease due to a giant corticotrophinoma. We performed whole exome sequencing of germline and tumour DNA, SNP array of tumour DNA and tumour immunohistochemistry in order to detect variants in candidate circadian/pituitary-associated genes. We identified a rare germline missense variant in the aryl hydrocarbon receptor (AHR) gene, which has previously been indirectly linked to pituitary tumorigenesis and clock system disruption. The AHR variant was found in a highly conserved site involved in phosphorylation. It was predicted to be damaging by multiple in silico tools and AHR tumour immunohistochemistry demonstrated loss of the normal nuclear staining pattern, suggestive of an inactivating mutation. We also found a novel, damaging germline missense variant in the retinoid X receptor gamma (RXRG) gene, multiple somatic chromosomal gains (including AHR), and a somatic mutational signature consistent with oncogenesis that may have acted synergistically with the AHR variant. CONCLUSIONS: This is the first report of an AHR variant with predicted pathogenicity in the pituitary adenoma setting. Our preliminary data suggest that the highly conserved AHR gene may represent a link between pituitary tumorigenesis, the hypothalamic-pituitary-adrenal axis and the clock system. Further research may indicate a role for the gene in the development of cyclical Cushing's disease.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Síndrome de Cushing/genética , Síndrome de Cushing/patologia , Polimorfismo de Nucleotídeo Único , Receptores de Hidrocarboneto Arílico/genética , Adenoma/sangue , Adenoma/genética , Adenoma/patologia , Síndrome de Cushing/sangue , Humanos , Hidrocortisona/sangue , Masculino , Pessoa de Meia-Idade , Neoplasias Hipofisárias/sangue , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/patologia , Prognóstico
15.
BMC Endocr Disord ; 20(1): 17, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31996211

RESUMO

BACKGROUND: Pituitary adenomas (PA) have an increased potential for relapse in one to 5 years after resection. In this study, we investigated the genetic differences in genomic DNA of primary and rapidly recurrent tumours in the same patient to explain the causality mechanisms of PA recurrence. CASE PRESENTATION: The patient was a 69-year-old female with non-functional pituitary macroadenoma with extension into the left cavernous sinus (Knosp grade 2) who underwent craniotomy and partial resection in August 2010. Two years later, the patient had prolonged tumour growth with an essential suprasellar extension (Knosp grade 2), and a second craniotomy with partial tumour resection was performed in September 2012. In both tumours, the KI-67 level was below 1.5%. Exome sequencing via semiconductor sequencing of patient germline DNA and somatic DNA from both tumours was performed. Tmap alignment and Platypus variant calling were performed followed by variant filtering and manual review with IGV software. We observed an increased load of missense variants in the recurrent PA tumour when compared to the original tumour. The number of detected variants increased from ten to 26 and potential clonal expansion of four variants was observed. Additionally, targeted SNP analysis revealed five rare missense SNPs with a potential impact on the function of the encoded proteins. CONCLUSIONS: In this case study, an SNP located in HRAS is the most likely candidate inducing rapid PA progression. The relapsed PA tumour had a higher variation load and fast tumour recurrence in this patient could be caused by clonal expansion of the leftover tumour tissue.


Assuntos
Adenoma/genética , Marcadores Genéticos , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Neoplasias Hipofisárias/genética , Polimorfismo de Nucleotídeo Único , Adenoma/patologia , Idoso , Feminino , Humanos , Neoplasias Hipofisárias/patologia , Prognóstico
16.
Cancer Cell ; 37(1): 123-134.e5, 2020 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-31883967

RESUMO

Pituitary neuroendocrine tumors (PitNETs) are common, with five main histological subtypes: lactotroph, somatotroph, and thyrotroph (POU1F1/PIT1 lineage); corticotroph (TBX19/TPIT lineage); and gonadotroph (NR5A1/SF1 lineage). We report a comprehensive pangenomic classification of PitNETs. PitNETs from POU1F1/PIT1 lineage showed an epigenetic signature of diffuse DNA hypomethylation, with transposable elements expression and chromosomal instability (except for GNAS-mutated somatotrophs). In TPIT lineage, corticotrophs were divided into three classes: the USP8-mutated with overt secretion, the USP8-wild-type with increased invasiveness and increased epithelial-mesenchymal transition, and the large silent tumors with gonadotroph transdifferentiation. Unexpected expression of gonadotroph markers was also found in GNAS-wild-type somatotrophs (SF1 expression), challenging the current definition of SF1/gonadotroph lineage. This classification improves our understanding and affects the clinical stratification of patients with PitNETs.


Assuntos
Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/genética , Neoplasias Hipofisárias/diagnóstico , Neoplasias Hipofisárias/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem da Célula , Aberrações Cromossômicas , Metilação de DNA , Endopeptidases/metabolismo , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Epigênese Genética , Epigenoma , Exoma , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Invasividade Neoplásica , Tumores Neuroendócrinos/patologia , Hipófise/metabolismo , Neoplasias Hipofisárias/patologia , Prognóstico , Transcriptoma , Ubiquitina Tiolesterase/metabolismo , Adulto Jovem
17.
Mol Cell Endocrinol ; 499: 110607, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31586652

RESUMO

The cAMP-PKA pathway plays an essential role in the pituitary gland, governing cell differentiation and survival, and maintenance of endocrine function. Somatotroph growth hormone transcription and release as well as cell proliferation are regulated by the cAMP-PKA pathway; cAMP-PKA pathway abnormalities are frequently detected in sporadic as well as in hereditary somatotroph tumors and more rarely in other pituitary tumors. Inactivating variants of the aryl hydrocarbon receptor-interacting protein (AIP)-coding gene are the genetic cause of a subset of familial isolated pituitary adenomas (FIPA). Multiple functional links between the co-chaperone AIP and the cAMP-PKA pathway have been described. This review explores the role of chaperones including AIP in normal pituitary function as well as in somatotroph tumors, and their interaction with the cAMP-PKA pathway.


Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Chaperonas Moleculares/metabolismo , Neoplasias Hipofisárias/metabolismo , Animais , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Chaperonas Moleculares/genética , Neoplasias Hipofisárias/genética , Transdução de Sinais
18.
Horm Metab Res ; 52(1): 8-24, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31863423

RESUMO

Pituitary adenomas represent approximately 15% of brain tumors; incidence is significantly on the increase due to widespread use of magnetic resonance imaging. Surgery remains the first-line treatment for most tumors overall. The role of dopaminergic agonists (DAs) and somatostatin receptor ligands (SRLs) in the treatment of pituitary adenomas is quite well established for prolactinomas and growth hormone (GH) excess. However, over the last decade new multi-receptor binding SRLs are increasingly used for treatment of acromegaly and Cushing's disease. SRLs/DA chimeric compounds seem to have enhanced potency and efficacy when compared to that of individual SRLs or DA receptor agonists according to preclinical data. However, following negative results, more research is needed to determine if this interesting mechanism will translate into positive clinical effects for acromegaly patients. Furthermore, new agents that block adrenal steroidogenesis have been developed in phase III clinical trials for Cushing's disease and several new compounds working at the pituitary level and/or blocking the glucocorticoid receptor are also in development. Combination therapy of drugs with similar or different mechanisms (possibly synergistic) are also on the increase. A growing awareness regarding all mechanisms involved in both control of pituitary secretion and cellular proliferation might allow for sole medical treatment of pituitary adenomas, especially macroadenomas, rather than surgery and/or radiation therapy, in the future. Moreover, the underlying decision on how to treat patients with pituitary adenomas should be individualized on a case-by-case basis with not only a goal of tumor shrinkage and biochemical control, but also of improving patients' quality of life.


Assuntos
Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Neoplasias Hipofisárias/tratamento farmacológico , Animais , Ensaios Clínicos como Assunto , Agonistas de Dopamina/administração & dosagem , Humanos , Hipersecreção Hipofisária de ACTH/genética , Hipersecreção Hipofisária de ACTH/metabolismo , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/metabolismo , Receptores de Somatostatina/agonistas
19.
BMC Med Genet ; 20(1): 185, 2019 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-31747893

RESUMO

BACKGROUND: Our purpose was to determine if SIRT1 (rs4746720, rs3740051) genotypes have an influence on the development of pituitary adenoma (PA). METHODS: The study group included 142 patients with pituitary adenoma (PA) and the control group consisted of 826 healthy people. The genotyping of SIRT1 (rs4746720, rs3740051) was carried out using the real-time polymerase chain reaction method. RESULTS: Statistically significant results were obtained in the analysis of SIRT1 rs3740051. Significant differences in genotype (G/G, G/A, A/A) distribution were obtained comparing patients with PA without recurrence and PA with recurrence (0, 17.9, 82.1% vs. 6.7, 6.7, 86.7%, respectively, p = 0.022). Also, statistically significant differences were observed when comparing the genotype (G/G, G/A, A/A) distribution in the non-invasive PA group and the invasive PA group (3.4, 25.9, 70.7% vs. 0, 8.3, 91.7%, respectively, p = 0.003), and allele G was less frequently observed in invasive PA, than in non-invasive PA (4.2% vs. 16.4%, p < 0,001). Further analysis revealed that G/A (OR = 0.261; 95% CI:0.099-0.689; p = 0.007) and each allele A (OR = 0.229; 95% CI:0.091-0.575; p = 0.002) were associated with lower odds of occurring an invasive PA. CONCLUSIONS: Our study revealed that SIRT1 rs3740051 is associated with PA recurrence and invasiveness. The haplotype containing alleles C-A in rs12778366-rs3740051 was found to be associated with increased odds of PA development as well.


Assuntos
Adenoma/genética , Neoplasias Hipofisárias/genética , Sirtuína 1/genética , Adenoma/metabolismo , Adenoma/patologia , Adulto , Idoso , Alelos , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Hormônios Hipofisários/metabolismo , Neoplasias Hipofisárias/metabolismo , Neoplasias Hipofisárias/patologia , Recidiva
20.
Ann Endocrinol (Paris) ; 80 Suppl 1: S19-S28, 2019 Sep.
Artigo em Francês | MEDLINE | ID: mdl-31606058

RESUMO

Multiple Endocrine Neoplasia Type 1 (NEM1) is related to mutations of the menin gene. It is an autosomal dominant disease. Its prevalence is about 1/30 000 with a hugh penetrance. There is no genotype-phenotype correlation. This hereditary syndrome is characterized by the presence of tumors of the endocrine system (parathyroid, endocrine pancreas, pituitary and adrenal gland). Other disorders have also been described (bronchial and thymic carcinoid tumor, breast cancer, skin lesions). Management must take into account the specificities of these pathologies in NEM1 compared to sporadic forms (young age at diagnosis, multiple lesions within the same gland, multi-focal disease). © 2019 Published by Elsevier Masson SAS. All rights reserved. Cet article fait partie du numéro supplément Les Must de l'Endocrinologie 2019 réalisé avec le soutien institutionnel de Ipsen-Pharma.


Assuntos
Congressos como Assunto , Endocrinologia/tendências , Neoplasia Endócrina Múltipla Tipo 1 , Tumor Carcinoide/diagnóstico , Tumor Carcinoide/epidemiologia , Tumor Carcinoide/genética , Tumor Carcinoide/terapia , Congressos como Assunto/organização & administração , Congressos como Assunto/tendências , Endocrinologia/métodos , Endocrinologia/organização & administração , Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/epidemiologia , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/terapia , Humanos , Neoplasia Endócrina Múltipla Tipo 1/diagnóstico , Neoplasia Endócrina Múltipla Tipo 1/epidemiologia , Neoplasia Endócrina Múltipla Tipo 1/genética , Neoplasia Endócrina Múltipla Tipo 1/terapia , Mutação , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/epidemiologia , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/terapia , Penetrância , Neoplasias Hipofisárias/diagnóstico , Neoplasias Hipofisárias/epidemiologia , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/terapia , Proteínas Proto-Oncogênicas/genética , Sociedades Médicas/organização & administração , Sociedades Médicas/normas , Sociedades Médicas/tendências
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