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1.
Oncogene ; 39(30): 5282-5291, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32561853

RESUMO

Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with limited therapeutic options. The lack of mouse models that recapitulate the genetics of ACC has hampered progress in the field. We analyzed The Cancer Genome Atlas (TCGA) dataset for ACC and found that patients harboring alterations in both p53/Rb and Wnt/ß-catenin signaling pathways show a worse prognosis compared with patients that harbored alterations in only one. To model this, we utilized the Cyp11b2(AS)Cre mouse line to generate mice with adrenocortical-specific Wnt/ß-catenin activation, Trp53 deletion, or the combination of both. Mice with targeted Wnt/ß-catenin activation or Trp53 deletion showed no changes associated with tumor formation. In contrast, alterations in both pathways led to ACC with pulmonary metastases. Similar to ACCs in humans, these tumors produced increased levels of corticosterone and aldosterone and showed a high proliferation index. Gene expression analysis revealed that mouse tumors exhibited downregulation of Star and Cyp11b1 and upregulation of Ezh2, similar to ACC patients with a poor prognosis. Altogether, these data show that altering both Wnt/ß-catenin and p53/Rb signaling is sufficient to drive ACC in mouse. This autochthonous model of ACC represents a new tool to investigate the biology of ACC and to identify new treatment strategies.


Assuntos
Neoplasias do Córtex Suprarrenal/genética , Modelos Animais de Doenças , Proteína Supressora de Tumor p53/genética , Via de Sinalização Wnt/genética , beta Catenina/genética , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/genética , Carcinoma Adrenocortical/patologia , Animais , Proliferação de Células/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Camundongos Knockout , Camundongos Transgênicos , Prognóstico
2.
Curr Opin Endocrinol Diabetes Obes ; 27(3): 177-186, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32304390

RESUMO

PURPOSE OF REVIEW: Adrenocortical tumor (ACT) is a rare disease with an annual worldwide incidence of 0.3-0.38/million children below 15 years old, and Brazilian population presents the highest incidence because of germline mutation in the TP53. Pediatric ACT is associated with virilizing features and hypercortisolism in most cases. Malignancy is defined when local invasion or metastasis is found, and it is associated with a poor prognosis. However, the correct and early diagnosis and treatment may impact on overall and disease-free survival. RECENT FINDINGS: A complete understanding of the disease and its singularities facilitates the assistance to the pediatric patient with ACT. The new insights about adrenal tumorigenesis have provided a better understanding of this disease. In this scenario, the era of molecular studies is leading to the refinement of the taxonomy, and it is offering the opportunity to discover new biomarkers and pathways of tumorigenesis, beyond the knowing ß-catenin, Insulin-like growth factor-II/IGF-IR, and the p53/Rb signaling. SUMMARY: The rarity of this disease makes it a real challenge. Here, we present a review focusing on clinical practice. A methodic approach aiming to clarify the diagnosis and a follow-up are suggested to guide physicians in the assistance of pediatrics patients, improving the prognosis.


Assuntos
Neoplasias do Córtex Suprarrenal/epidemiologia , Neoplasias do Córtex Suprarrenal/terapia , Carcinoma Adrenocortical/epidemiologia , Carcinoma Adrenocortical/terapia , Adolescente , Neoplasias do Córtex Suprarrenal/diagnóstico , Neoplasias do Córtex Suprarrenal/genética , Carcinoma Adrenocortical/diagnóstico , Carcinoma Adrenocortical/genética , Idade de Início , Transformação Celular Neoplásica/genética , Criança , Pré-Escolar , Endocrinologia/métodos , Endocrinologia/tendências , Mutação em Linhagem Germinativa , Humanos , Lactente , Recém-Nascido , Oncologia/métodos , Oncologia/tendências , Pediatria/métodos , Pediatria/tendências
3.
PLoS One ; 15(4): e0231665, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32287321

RESUMO

BACKGROUND: Many genomic analyses of cortisol-producing adrenocortical carcinoma (ACC) have been reported, but very few have come from East Asia. The first objective of this study is to verify the genetic difference with the previous reports by analyzing targeted deep sequencing of 7 Japanese ACC cases using next-generation sequencing (NGS). The second objective is to compare the somatic variant findings identified by NGS analysis with clinical and pathological findings, aiming to acquire new knowledge about the factors that contribute to the poor prognosis of ACC and to find new targets for the treatment of ACC. METHOD: DNA was extracted from ACC tissue of seven patients and two reference blood samples. Targeted deep sequencing was performed using the MiSeq system for 12 genes, and the obtained results were analyzed using MuTect2. The hypothesis was obtained by integrating the somatic variant findings with clinical and pathological data, and it was further verified using The Cancer Genome Atlas (TCGA) dataset for ACC. RESULTS: Six possible pathogenic and one uncertain significance somatic variants including a novel PRKAR1A (NM_002734.4):c.545C>A (p.T182K) variant were found in five of seven cases. By integrating these data with pathological findings, we hypothesized that cases with TP53 variants were more likely to show atypical mitotic figures. Using TCGA dataset, we found that atypical mitotic figures were associated with TP53 somatic variant, and mRNA expression of CCNB2 and AURKA was significantly high in TP53 mutated cases and atypical mitotic figure cases. CONCLUSION: We believe this is the first report that discusses the relationship between atypical mitotic figures and TP53 somatic variant in ACC. We presumed that overexpression of CCNB2 and AURKA mRNA may cause atypical mitosis in TP53 somatic mutated cases. Because AURKA is highly expressed in atypical mitotic cases, it may be an appropriate indicator for AURKA inhibitors.


Assuntos
Neoplasias do Córtex Suprarrenal/genética , Carcinoma Adrenocortical/genética , Aurora Quinase A/genética , Ciclina B2/genética , Mitose , Regulação para Cima , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/patologia , Adulto , Aurora Quinase A/metabolismo , Ciclina B2/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteína Supressora de Tumor p53/genética
4.
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
5.
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
6.
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
7.
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
8.
J Clin Endocrinol Metab ; 105(3)2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31970420

RESUMO

CONTEXT: The WNT/ß-catenin pathway is central to the pathogenesis of various human diseases including those affecting bone development and tumor progression. OBJECTIVE: To evaluate the role of a gain-of-function variant in CTNNB1 in a child with a sclerosing bone dysplasia and an adrenocortical adenoma. DESIGN: Whole exome sequencing with corroborative biochemical analyses. PATIENTS: We recruited a child with a sclerosing bone dysplasia and an adrenocortical adenoma together with her unaffected parents. INTERVENTION: Whole exome sequencing and performance of immunoblotting and luciferase-based assays to assess the cellular consequences of a de novo variant in CTNNB1. MAIN OUTCOME MEASURE(S)/RESULT: A de novo variant in CTNNB1 (c.131C>T; p.[Pro44Leu]) was identified in a patient with a sclerosing bone dysplasia and an adrenocortical adenoma. A luciferase-based transcriptional assay of WNT signaling activity verified that the activity of ß-catenin was increased in the cells transfected with a CTNNB1p.Pro44Leu construct (P = 4.00 × 10-5). The ß-catenin p.Pro44Leu variant was also associated with a decrease in phosphorylation at Ser45 and Ser33/Ser37/Thr41 in comparison to a wild-type (WT) CTNNB1 construct (P = 2.16 × 10-3, P = 9.34 × 10-8 respectively). CONCLUSION: Increased ß-catenin activity associated with a de novo gain-of-function CTNNB1 variant is associated with osteosclerotic phenotype and adrenocortical neoplasia.


Assuntos
Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/patologia , Doenças do Desenvolvimento Ósseo/patologia , Mutação , beta Catenina/genética , Neoplasias do Córtex Suprarrenal/genética , Carcinoma Adrenocortical/genética , Doenças do Desenvolvimento Ósseo/genética , Feminino , Humanos , Recém-Nascido , Masculino , Linhagem , Fenótipo , Prognóstico , Sequenciamento Completo do Exoma
9.
J Clin Endocrinol Metab ; 105(3)2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31789380

RESUMO

CONTEXT: Aldosterone-producing adrenocortical adenomas (APAs) are mainly composed of clear (lipid rich) and compact (eosinophilic) tumor cells. The detailed association between these histological features and somatic mutations (KCNJ5, ATP1A1, ATP2B3, and CACNA1D) in APAs is unknown. OBJECTIVE: To examine the association between histological features and individual genotypes in APAs. METHODS: Examination of 39 APAs subjected to targeted next-generation sequencing (11 KCNJ5, 10 ATP1A1, 10 ATP2B3, and 8 CACNA1D) and quantitative morphological and immunohistochemical (CYP11B2 and CYP17A1) analyses using digital imaging software. RESULTS: KCNJ5- and ATP2B3-mutated APAs had clear cell dominant features (KCNJ5: clear 59.8% [54.4-64.6%] vs compact 40.2% (35.4-45.6%), P = .0022; ATP2B3: clear 54.3% [48.2-62.4 %] vs compact 45.7% (37.6-51.8 %), P = .0696). ATP1A1- and CACNA1D-mutated APAs presented with marked intratumoral heterogeneity. A significantly positive correlation of immunoreactivity was detected between CYP11B2 and CYP17A1 in tumor cells of KCNJ5-mutated APAs (P = .0112; ρ = 0.7237), in contrast, significantly inverse correlation was detected in ATP1A1-mutated APAs (P = .0025; ρ = -0.8667). CONCLUSION: KCNJ5-mutated APAs, coexpressing CYP11B2 and CYP17A1, were more deviated in terms of zonation-specific differentiation of adrenocortical cells than ATP1A1- and ATP2B3-mutated APAs.


Assuntos
Neoplasias do Córtex Suprarrenal/genética , Adenoma Adrenocortical/genética , Mutação , Neoplasias do Córtex Suprarrenal/patologia , Adenoma Adrenocortical/patologia , Adulto , Aldosterona/metabolismo , Canais de Cálcio Tipo L/genética , Feminino , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/genética , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , ATPases Transportadoras de Cálcio da Membrana Plasmática/genética , ATPase Trocadora de Sódio-Potássio/genética
10.
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
11.
Surgery ; 167(1): 224-232, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31522749

RESUMO

BACKGROUND: Adrenocortical carcinoma is an aggressive malignancy with a low but variable overall survival rate. The role of in adrenocortical carcinoma is poorly understood. Thus, in this study we performed long noncoding RNA expression profiling in adrenocortical carcinomas, adrenocortical adenomas, and normal adrenal cortex. METHODS: Long noncoding RNA expression profile using Human LncRNA/mRNA Expression Microarray V3.0 (Arraystar, Inc, Rockville, MD) was analyzed in samples from 11 adrenocortical adenomas, 9 adrenocortical carcinomas, and 5 normal adrenal cortex. Differentially expressed long noncoding RNAs were validated using TaqMan, real-time quantitative polymerase chain reaction with additional samples. The dataset from the adrenocortical carcinoma Cancer Genome Atlas Programproject was used to evaluate the prognostic utility of long noncoding RNAs. RESULTS: Unsupervised hierarchical clustering showed distinct clustering of adrenocortical carcinoma samples compared with normal adrenal cortex and adrenocortical adenoma samples by long noncoding RNA expression profiles. A total of 874 long noncoding RNAs were differentially expressed between adrenocortical carcinoma and normal adrenal cortex. LINC00271 expression level was associated with prognosis, patients with low LINC00271 expression survived a shorter time than patients with high LINC00271 expression. Low LINC00271 expression was positively associated with WNT signaling, cell cycle, and chromosome segregation pathways. CONCLUSION: Adrenocortical carcinoma has a distinct long noncoding RNA expression profile. LINC00271 is downregulated in adrenocortical carcinoma and appears to be involved in biologic pathways commonly dysregulated in adrenocortical carcinoma.


Assuntos
Neoplasias do Córtex Suprarrenal/genética , Carcinoma Adrenocortical/genética , Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , RNA Longo não Codificante/metabolismo , Córtex Suprarrenal/patologia , Neoplasias do Córtex Suprarrenal/mortalidade , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/mortalidade , Carcinoma Adrenocortical/patologia , Adulto , Idoso , Biomarcadores Tumorais/genética , Ciclo Celular/genética , Segregação de Cromossomos/genética , Variações do Número de Cópias de DNA , Regulação para Baixo , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Tempo , Via de Sinalização Wnt/genética
12.
Surgery ; 167(1): 233-240, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31561992

RESUMO

INTRODUCTION: Adrenocortical carcinoma is an aggressive cancer with a poor prognosis. Long noncoding RNAs are differentially expressed in cancer patients and contribute to cellular homeostasis, survival, and metastasis. We hypothesize that our novel C-terminal Hsp90 inhibitor KU758 can effectively target adrenocortical carcinoma cells and favorably alter long noncoding RNA expression. METHODS: Cell viability after KU758 treatment was measured in the adrenocortical carcinoma cell lines SW13, RL251, and NCI-H295R by MTS assay. Cellular mobility and metastatic potential after Hsp90 inhibition was measured through migration, invasion, and aggregate formation assays. ß-catenin activity in NCI-H295R cells was determined by immunofluorescence and polymerase chain reaction. Long noncoding RNA expression was determined by polymerase chain reaction array after Hsp90 inhibition. RESULTS: KU758 is selective for adrenocortical carcinoma cells with IC50 values of 0.6 to 2.4 µM. KU758 treatment can effectively reduce migration, invasion, and aggregate formation in NCI-H295R and SW13 cells. ß-catenin activity is decreased after treatment with KU758. Treatment with KU758 is associated with overall statistically significant upregulation of long noncoding RNA expression, including the tumor suppressor GAS5, which is implicated in the ß-catenin and mammalian target of rapamycin pathways in adrenocortical carcinoma. CONCLUSION: The novel C-terminal Hsp90 inhibitor KU758 is effective in the treatment of adrenocortical carcinoma cells and can significantly alter long noncoding RNA expression for tumor suppression.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Antineoplásicos/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , RNA Longo não Codificante/metabolismo , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/genética , Carcinoma Adrenocortical/patologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Concentração Inibidora 50 , Regulação para Cima/efeitos dos fármacos
13.
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
14.
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
15.
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
16.
Surg Pathol Clin ; 12(4): 967-995, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31672302

RESUMO

Adrenocortical tumors range from primary bilateral micronodular or macronodular forms of adrenocortical disease to conventional adrenocortical adenomas and carcinomas. Accurate classification of these neoplasms is critical given the varied pathogenesis, clinical behavior, and outcome of these different lesions. Confirmation of adrenocortical origin, diagnosing malignancy, providing relevant prognostic information in adrenocortical carcinoma, and correlation of laboratory results with clinicopathologic findings are among the important responsibilities of pathologists who evaluate these lesions. This article focuses on a practical approach to the evaluation of adrenocortical tumors with an emphasis on clinical and imaging findings, morphologic characteristics, and multifactorial diagnostic schemes and algorithms.


Assuntos
Neoplasias do Córtex Suprarrenal/diagnóstico , Adenoma Adrenocortical/diagnóstico , Carcinoma Adrenocortical/diagnóstico , Síndrome de Cushing/etiologia , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/patologia , Adenoma Adrenocortical/genética , Adenoma Adrenocortical/patologia , Carcinoma Adrenocortical/genética , Carcinoma Adrenocortical/patologia , Síndrome de Cushing/patologia , Triagem de Portadores Genéticos , Guias como Assunto , Humanos , Imuno-Histoquímica
17.
Exp Suppl ; 111: 149-169, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31588532

RESUMO

Adrenocortical malignancies can occur in the context of several tumor predisposition syndromes.The Carney complex (CNC) is responsible for the majority of primary pigmented nodular adrenal diseases and is more rarely associated with adrenocortical carcinoma (ACC). Other core manifestations of CNC include cardiac and cutaneous myxomas, lentiginosis, somatotroph pituitary adenomas, Sertoli tumors, melanocytic schwannoma, and thyroid, breast, and bone tumors. CNC is mostly due to germline inactivating mutations of PRKAR1A.The majority of childhood ACC are related to genetic predisposition. The Beckwith-Wiedemann syndrome (BWS) is an overgrowth and tumor predisposition syndrome due to genetic or epigenetic alterations at the 11p15 locus. Classical tumor spectrum of BWS includes embryonal tumors and childhood ACC. The Li-Fraumeni syndrome (LFS) is a devastating tumor predisposition syndrome, due to germline inactivating mutations of TP53, and characterized by a high, various, and early-onset cancer risk. LFS spectrum includes premenopausal breast cancer, soft-tissue sarcoma, osteosarcoma, central nervous system tumor, and ACC, accounting for 50-80% of pediatric cases. Finally, germline predisposition affects up to 10% of adult ACC patients, mostly in part of LFS and Lynch syndrome.This chapter focuses on the diagnosis, screening, and management of adrenal tumors in part of these tumor predisposition syndromes.


Assuntos
Neoplasias do Córtex Suprarrenal/genética , Carcinoma Adrenocortical/genética , Síndrome de Beckwith-Wiedemann/genética , Complexo de Carney/genética , Síndrome de Li-Fraumeni/genética , Predisposição Genética para Doença , Humanos
18.
Arkh Patol ; 81(5): 92-96, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31626211

RESUMO

Studies of the last decade have demonstrated that the morphological and immunophenotypic patterns of adrenocortical carcinoma (ACC) have a high heterogeneity in both the occurrence of various tumors and the development of a solitary tumor. Carcinogenesis of ACC, like most neoplastic processes, is associated with mutations in at least 15 driver genes, with a wide range of chromosomal aberrations, epigenomic changes, and alterations of the microRNA profile. According to the literature, isolated genetic damage is also insufficient for the manifestation of the malignant phenotype of adrenocortical cells. Knudson's two-hit hypothesis is implemented in at least germline mutations: the development of ACC requires a second genetic event occurring in somatic cells, which leads to inactivation of the second allele of the gene. ACC is an extremely heterogeneous disease, which determines the complexity of differential diagnosis with benign adrenocortical tumors and that of prediction of the clinical course. Another no less important issue is the lack of valid predictors for the efficacy of mitotane, the use of which may be associated with severe adverse effects.


Assuntos
Neoplasias do Córtex Suprarrenal/genética , Carcinoma Adrenocortical/genética , Neoplasias do Córtex Suprarrenal/diagnóstico , Carcinoma Adrenocortical/diagnóstico , Carcinogênese , Marcadores Genéticos , Humanos
19.
JCI Insight ; 4(17)2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31484828

RESUMO

Recent genetic examinations and multisteroid profiles have provided the basis for subclassification of aldosterone-producing adenomas (APAs). The objective of the current study was to produce a comprehensive, high-resolution mass spectrometry imaging (MSI) map of APAs in relation to morphometry, immunohistochemical profiles, mutational status, and clinical outcome. The study cohort comprised 136 patients with unilateral primary aldosteronism. Matrix-assisted laser desorption/ionization-Fourier transform-ion cyclotron resonance MSI was conducted, and metabolite profiles were analyzed with genotype/phenotype information, including digital image analysis from morphometry and IHC of steroidogenic enzymes. Distinct molecular signatures between KCNJ5- and CACNA1D-mutated APAs with significant differences of 137 metabolites, including metabolites of purine metabolism and steroidogenesis, were observed. Intratumor concentration of 18-oxocortisol and 18-hydroxycortisol were inversely correlated with the staining intensity of CYP11B1. Lower staining intensity of CYP11B1 and higher levels of 18-oxocortisol were associated with a higher probability of complete clinical success after surgery. The present study demonstrates distinct metabolomic profiles of APAs in relation to tumor genotype. In addition, we reveal an inverse correlation between cortisol derivatives and CYP11B1 and the impact of 18-oxocortisol and CYP11B1 on clinical outcome, which provides unprecedented insights into the pathophysiology, clinical features, and steroidogenesis of APAs.


Assuntos
Adenoma/metabolismo , Neoplasias do Córtex Suprarrenal/metabolismo , Adenoma Adrenocortical/metabolismo , Aldosterona/metabolismo , Metabolômica/métodos , Adenoma/genética , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/patologia , Adenoma Adrenocortical/genética , Adenoma Adrenocortical/patologia , Adulto , Aldosterona/genética , Canais de Cálcio Tipo L/metabolismo , Estudos de Coortes , Feminino , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/metabolismo , Genótipo , Humanos , Hidrocortisona/análogos & derivados , Hidrocortisona/metabolismo , Hiperaldosteronismo/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Esteroide 11-beta-Hidroxilase/metabolismo
20.
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
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