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1.
Exp Suppl ; 111: 171-211, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31588533

RESUMO

Pituitary tumours are relatively common in the general population. Most often they occur sporadically, with somatic mutations accounting for a significant minority of somatotroph and corticotroph adenomas. Pituitary tumours can also develop secondary to germline mutations as part of a complex syndrome or as familial isolated pituitary adenomas. Tumours occurring in a familial setting may present at a younger age and can behave more aggressively with resistance to treatment. This chapter will focus on the genetics and molecular pathogenesis of pituitary tumours.


Assuntos
Neoplasias Hipofisárias/genética , Adenoma Hipofisário Secretor de ACT/genética , Mutação em Linhagem Germinativa , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Humanos
2.
Arch Endocrinol Metab ; 63(4): 385-393, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31365626

RESUMO

INTRODUCTION: Gigantism is a rare pediatric disease characterized by increased production of growth hormone (GH) before epiphyseal closure, that manifests clinically as tall stature, musculoskeletal abnormalities, and multiple comorbidities. MATERIALS AND METHODS: Case series of 6 male patients with gigantism evaluated at the Endocrinology Service of Hospital de San José (Bogotá, Colombia) between 2010 and 2016. RESULTS: All patients had macroadenomas and their mean final height was 2.01 m. The mean age at diagnosis was 16 years, and the most common symptoms were headache (66%) and hyperhidrosis (66%). All patients had acral changes, and one had visual impairment secondary to compression of the optic chiasm. All patients underwent surgery, and 5 (83%) required additional therapy for biochemical control, including radiotherapy (n = 4, 66%), somatostatin analogues (n = 5, 83%), cabergoline (n = 3, 50%), and pegvisomant (n = 2, 33%). Three patients (50%) achieved complete biochemical control, while 2 patients showed IGF-1 normalization with pegvisomant. Two patients were genetically related and presented a mutation in the aryl hydrocarbon receptor-interacting protein (AIP) gene (pathogenic variant, c.504G>A in exon 4, p.Trp168*), fulfilling the diagnostic criteria of familial isolated pituitary adenoma. CONCLUSIONS: This is the largest case series of patients with gigantism described to date in Colombia. Transsphenoidal surgery was the first-choice procedure, but additional pharmacological therapy was usually required. Mutations in the AIP gene should be considered in familial cases of GH-producing adenomas.


Assuntos
Adenoma/terapia , Gigantismo/terapia , Neoplasias Hipofisárias/terapia , Adenoma/diagnóstico , Adolescente , Colômbia , Seguimentos , Gigantismo/diagnóstico , Hormônio do Crescimento/sangue , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Humanos , Fator de Crescimento Insulin-Like I/análise , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Mutação/genética , Linhagem , Neoplasias Hipofisárias/diagnóstico , Estudos Retrospectivos , Distribuição por Sexo , Resultado do Tratamento , Adulto Jovem
3.
Endocr J ; 66(5): 403-408, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-30814395

RESUMO

GH-secreting pituitary adenomas (GHomas) are rare in the pediatric population. Guanine nucleotide-binding protein, alpha stimulating (GNAS) somatic mutations are often found in patients with GHoma. Here, we report an 8-year-old girl with GH-secreting pituitary adenoma successfully treated by operative tumor resection and postoperative treatment with octreotide long-acting release (LAR). Tumor DNA sequence analysis revealed a somatic heterozygous c.680A>T (p.Gln227Leu) mutation in GNAS. We reviewed 1,084 cases of GHomas, 409 (37.7%) of which harbored GNAS mutations. In pediatrics cases, aged 15 years or younger, 11 harbored a GNAS mutation, and GNAS p.Arg201Cys was identified in five cases. No other cases of codon 227 mutation were detected. These cases suggest that, in pediatric patients, the clinical features of GHoma may differ from those observed in adults. This is possibly related to octreotide or dopamine agonist resistance. Of six patients with surgical resistance, only one was reactive when treated with octreotide. Our case shows that octreotide LAR is an effective choice for treating GNAS-induced GHoma. This is the first report detailing the effectiveness of octreotide LAR in a GNAS codon 227 mutation-induced GHoma in a pediatric case. Examination of the relationship between genetic variation and clinical features in pediatric patients will enable us to assess the long-term effects of surgical and medical treatment of GHomas.


Assuntos
Cromograninas/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Mutação , Neoplasias Hipofisárias/genética , Prolactinoma/genética , Criança , Análise Mutacional de DNA , Feminino , Adenoma Hipofisário Secretor de Hormônio do Crescimento/patologia , Humanos , Neoplasias Hipofisárias/patologia , Prolactinoma/patologia
5.
Pathobiology ; 86(2-3): 128-134, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30630164

RESUMO

OBJECTIVES: Pituitary adenomas (PAs) may rarely occur in well-defined hereditary conditions, like multiple endocrine neoplasia type 1 (MEN1) syndrome and familial isolated pituitary adenoma (FIPA) associated with germline mutations in MEN1 and AIP, respectively. This study aimed to assess MEN1 genetic abnormalities in AIP mutation-negative FIPA patients, not associated with MEN1 components. METHODS: Among 20 patients evaluated in 13 FIPA families, 12 were previously reported as AIP mutation-negative. In this study, 6 new families with 8 patients were recruited. All patients were subjected to multiplex ligation-dependent probe amplification to detect copy number variations in AIP and MEN1, and AIP sequencing was performed in additional patients. AIP mutation-negative patients were subjected to MEN1 sequencing. RESULTS: Our cohort revealed only 3 novel heterozygous MEN1 variants including c.1846T>A p.(*616Argext*21), rs778272737:T>C, and rs972128957:C>T in 2 families, with patients diagnosed with Cushing disease, nonfunction al adenoma, and acromegaly, respectively. Among them, c.1846T>A p. (*616Argext*21) is a stop codon read-through, whereas the others are 3'UTR variations. MEN1 variation frequency was detected as 15%. CONCLUSIONS: MEN1 alterations can be of significance in FIPA patients and screening could be offered to AIP mutation-negative patients without MEN1 features. Further studies are needed to clarify the role of MEN1 in FIPA patients.


Assuntos
Variação Genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasia Endócrina Múltipla Tipo 1/genética , Neoplasias Hipofisárias/genética , Adolescente , Adulto , Instituições de Assistência Ambulatorial , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Turquia , Adulto Jovem
6.
Minerva Endocrinol ; 44(2): 109-128, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30650942

RESUMO

Acromegaly is a chronic systemic disease mainly caused by a growth hormone (GH)-secreting pituitary neuroendocrine tumor (PitNETs), which is associated with many health complications and increased mortality when not adequately treated. Transsphenoidal surgery is considered the treatment of choice in GH-secreting PitNETs, but patients in whom surgery cannot be considered or with persistent disease after surgery require medical therapy. Treatment with available synthetic somatostatin analogues (SSAs) is considered the mainstay in the medical management of acromegaly which exert their beneficial effects through the binding to a family of G-protein coupled receptors encoded by 5 genes (SSTR1-5). However, although it has been demonstrated that the SST1-5 receptors are physically present in tumor cells, SSAs are in many cases ineffective (i.e. approximately 10-30% of patients with GH-secreting PitNET are unresponsive to SSAs), suggesting that other cellular/molecular determinants could be essential for the response to the pharmacological treatment in patients with GH-secreting PitNETs. Therefore, the scrutiny of these determinants might be used for the identification of subgroups of patients in whom an appropriate pharmacological treatment can be successfully employed (responders vs. non-responders). In this review, we will describe some of the existing, classical and novel, genetic and molecular determinants involved in the response of patients with GH-secreting PitNETs to the available therapeutic treatments, as well as new molecular/therapeutic approaches that could be potentially useful for the treatment of GH-secreting PitNETs.


Assuntos
Acromegalia/tratamento farmacológico , Acromegalia/genética , Adenoma/tratamento farmacológico , Adenoma/genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Humanos , Neoplasias Hipofisárias/complicações
7.
J Endocrinol ; 240(2): R21-R45, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30530903

RESUMO

While 95% of pituitary adenomas arise sporadically without a known inheritable predisposing mutation, in about 5% of the cases they can arise in a familial setting, either isolated (familial isolated pituitary adenoma or FIPA) or as part of a syndrome. FIPA is caused, in 15-30% of all kindreds, by inactivating mutations in the AIP gene, encoding a co-chaperone with a vast array of interacting partners and causing most commonly growth hormone excess. While the mechanisms linking AIP with pituitary tumorigenesis have not been fully understood, they are likely to involve several pathways, including the cAMP-dependent protein kinase A pathway via defective G inhibitory protein signalling or altered interaction with phosphodiesterases. The cAMP pathway is also affected by other conditions predisposing to pituitary tumours, including X-linked acrogigantism caused by duplications of the GPR101 gene, encoding an orphan G stimulatory protein-coupled receptor. Activating mosaic mutations in the GNAS gene, coding for the Gα stimulatory protein, cause McCune-Albright syndrome, while inactivating mutations in the regulatory type 1α subunit of protein kinase A represent the most frequent genetic cause of Carney complex, a syndromic condition with multi-organ manifestations also involving the pituitary gland. In this review, we discuss the genetic and molecular aspects of isolated and syndromic familial pituitary adenomas due to germline or mosaic mutations, including those secondary to AIP and GPR101 mutations, multiple endocrine neoplasia type 1 and 4, Carney complex, McCune-Albright syndrome, DICER1 syndrome and mutations in the SDHx genes underlying the association of familial paragangliomas and phaeochromocytomas with pituitary adenomas.


Assuntos
Adenoma/genética , Mutação em Linhagem Germinativa , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Mosaicismo , Neoplasias Hipofisárias/genética , Adenoma/metabolismo , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/metabolismo , Predisposição Genética para Doença/genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Hipofisárias/metabolismo , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo
8.
Minerva Endocrinol ; 44(2): 137-142, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30531696

RESUMO

Silent somatotroph pituitary neuroendocrine tumors (or silent growth hormone pituitary neuroendocrine tumors, SGH-PitNET) are neoplasias with positive immunostaining for growth hormone (GH), in patients with no signs and symptoms of acromegaly nor biochemical evidence of GH hypersecretion. From a clinical stand-point they are considered and managed as non-functioning pituitary tumors, since they usually come to evidence due to mass-effects (headache, visual impairment, hypopituitarism) or as asymptomatic pituitary incidentalomas. SGH-PitNET have deserved little attention in the medical literature, and no specific guidelines exist regarding their management. However, identification of a particular tumor lineage through immunostaining patterns of non-functioning pituitary tumors may determine postoperative medical therapy in the near future. This review updates the current knowledge about the epidemiologic, clinical, pathological and molecular characteristics of this particular type of pituitary tumors.


Assuntos
Adenoma/terapia , Adenoma Hipofisário Secretor de Hormônio do Crescimento/terapia , Adenoma/epidemiologia , Adenoma/genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/epidemiologia , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Humanos
9.
Ann Endocrinol (Paris) ; 80(2): 96-100, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30318257

RESUMO

OBJECTIVES: This study analyzed the KISS1 c.-145delA (rs5780218) promoter polymorphism in a cohort of patients with growth hormone secreting pituitary adenoma (somatotropinoma) and controls, to investigate its role in the incidence of acromegaly and to assess patient/tumor characteristics. Material and methods rs5780218 allelic and genotypic distributions were compared between 49 somatotropinoma patients and 167 healthy controls. rs5780218 was also assessed in relation to patient characteristics and tumor aggressiveness, as characterized by tumor invasion and resistance to conventional therapy. The relationship between KISS1 mRNA expression and the rs5780218 genotype was also assessed in available pituitary tumor samples. RESULTS: The homozygous -/- variant genotype was associated with high rates of somatotropinoma (P<0.01), but not with tumor invasiveness, patient characteristics or hormonal remission. KISS1 mRNA expression was much lower in somatotropinomas carrying the deleted allele than in homozygous wild type AA. CONCLUSIONS: In this pilot study, the rs5780218 promoter polymorphism was evaluated in pituitary adenoma, and showed a possible association with the incidence of somatotropinoma but not with tumor progression.


Assuntos
Adenoma/genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Kisspeptinas/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas/genética , Adenoma/epidemiologia , Adenoma/patologia , Adulto , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Adenoma Hipofisário Secretor de Hormônio do Crescimento/epidemiologia , Adenoma Hipofisário Secretor de Hormônio do Crescimento/patologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Polimorfismo de Nucleotídeo Único/fisiologia , Fatores de Risco , Adulto Jovem
10.
World Neurosurg ; 123: e45-e59, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30447469

RESUMO

BACKGROUND: Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene were identified in nearly 20% of families with familial isolated pituitary adenoma. Some variants of AIP have been confirmed to induce tumor cell proliferation and invasiveness; however, the mechanism is still unclear. METHODS: A novel missense mutation (c.512C>T, p.T171I) was discovered in 3 patients from a Chinese family with familial isolated pituitary adenoma. In silico and multiplex ligation-dependent probe amplification analysis predicted the mutation to be pathogenic. GH3 and 293FT cell lines were used to verify the variant's effect on cell proliferation (Cell Counting Kit-8), invasiveness (Transwell) and growth hormone (GH) secretion (enzyme-linked immunosorbent assay) by transfection with different vectors: control, blank vector, wild-type AIP, p.T171I variant (experimental group), p.Q315* variant, and AIP small interfering RNA. Furthermore, Zac1, Sstr2, interleukin (IL)-6, and Stat3/phosphorylation-Stat3 expression (reverse transcription polymerase chain reaction, Western blot) in each group was also evaluated. RESULTS: The experimental group, p.Q315* variant group, and AIP small interfering RNA-overexpressing group promoted cell proliferation at 24 and 48 hours, respectively (compared with the control group; P < 0.01 for both). Similarly, the cells in the experimental group manifested more invasion and GH secretion compared with the control group (P < 0.01 and P < 0.05, respectively). Furthermore, the experimental group cells expressed less Sstr2 (a prerequisite for the responsiveness to somatostatin analogues) and Zac1 (tumor suppressor gene), but more IL-6 and phosphorylated-Stat3 (GH-secretion related). CONCLUSIONS: The novel AIP mutation c.512C>T (p.T171I) is a pathogenic variant that promoted cell proliferation, invasiveness, and GH secretion through regulation of Sstr2, Zac1, and IL-6/phosphorylated-Stat3 expression.


Assuntos
Adenoma/genética , Adenoma/fisiopatologia , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/fisiopatologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação de Sentido Incorreto , Adenoma/diagnóstico por imagem , Adenoma/patologia , Adulto , Animais , Linhagem Celular , Proliferação de Células/fisiologia , Criança , Biologia Computacional , Feminino , Hormônio do Crescimento/metabolismo , Adenoma Hipofisário Secretor de Hormônio do Crescimento/diagnóstico por imagem , Adenoma Hipofisário Secretor de Hormônio do Crescimento/patologia , Humanos , Invasividade Neoplásica/genética , Invasividade Neoplásica/fisiopatologia , Ratos
11.
Endocrine ; 63(1): 182-187, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30155846

RESUMO

BACKGROUND: Pituitary adenomas and paragangliomas/pheocromocytomas are rare endocrine tumours, which can be sporadic or familial. During many years their coexistence in the same individual was considered a coincidental finding. However, an association between these two entities was recently demonstrated, with the possible involvement of SDHx genes. CASE REPORT: We describe a 57-year-old female patient, who was under surveillance since 1997 for a malignant paraganglioma with vertebral bone metastasis, and harboured a germline frameshift mutation in exon 6 of SDHB gene [c.587-591DelC]. Seventeen years later, she was diagnosed with acromegaly and underwent transesphenoidal endoscopic resection of a somatotropinoma. Three months after surgery she started treatment with lanreotide for residual disease. Despite initial good response, she developed resistance to first generation of somatostatin analogues and treatment had to be switched to pegvisomant. In the immunohistochemical staining, the pituitary adenoma was positive for SDHA expression, while SDHB showed an heterogeneous staining pattern, with areas markedly positive and others with positive and negative cells. CONCLUSIONS: Our findings provide useful data for understanding the link between paragangliomas/pheocromocytomas and somatotropinomas. While we confirm the well-established link between SDHB mutations and paragangliomas/pheocromocytomas, particularly with malignant paragangliomas, the preservation-at least partially-of SDHB expression in the somatotropinoma tissue does not allow drawing definite conclusions about the involvement of the SDHB mutation in pituitary adenoma.


Assuntos
Adenoma/genética , Neoplasias das Glândulas Endócrinas/genética , Mutação da Fase de Leitura/genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Paraganglioma/genética , Succinato Desidrogenase/genética , Acromegalia/etiologia , Adenoma/complicações , Adenoma/patologia , Terapia Combinada , Neoplasias das Glândulas Endócrinas/complicações , Neoplasias das Glândulas Endócrinas/patologia , Éxons/genética , Feminino , Mutação em Linhagem Germinativa , Adenoma Hipofisário Secretor de Hormônio do Crescimento/complicações , Adenoma Hipofisário Secretor de Hormônio do Crescimento/patologia , Humanos , Pessoa de Meia-Idade , Paraganglioma/complicações , Paraganglioma/patologia , Linhagem
12.
Cancer Lett ; 435: 101-109, 2018 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-30098401

RESUMO

An efficient intracellular response to somatostatin analogs (SSA) in pituitary tumors requires filamin A (FLNA). Since cAMP pathway plays an important role in GH-secreting pituitary tumors pathogenesis and FLNA is phosphorylated by PKA on S2152, aim of this study was to investigate in tumoral somatotrophs the impact of cAMP pathway activation and SSA stimulation on FLNA phosphorylation and the consequences on SST2 function. We found a PKA-mediated increase (2-fold) and SST2 agonist-induced decrease (-50%) of FLNA phosphorylation in GH3, GH4C1 and primary somatotroph tumor cells. This modification regulates FLNA function. Indeed, phosphomimetic S2152D FLNA mutant, but not phosphodeficient S2152A, abolished the known SSA antitumoral effects, namely: 1) inhibition of cell proliferation, reduction of cyclin D3 and increase of p27; 2) increase of cell apoptosis; 3) inhibition of cell migration via RhoA activation and cofilin phosphorylation. Coimmunoprecipitation and immunofluorescence assays showed that S2152A FLNA was recruited to activated SST2, whereas S2152D FLNA constitutively bound SST2 on the plasma membrane, but prevented Gαi proteins recruitment to SST2. In conclusion, we demonstrated that FLNA phosphorylation, promoted by cAMP pathway activation and inhibited by SSA, prevented SST2 signaling in GH-secreting tumoral pituitary cells.


Assuntos
AMP Cíclico/metabolismo , Filaminas/metabolismo , Adenoma Hipofisário Secretor de Hormônio do Crescimento/metabolismo , Neoplasias Hipofisárias/metabolismo , Proteínas Quinases/metabolismo , Receptores de Somatostatina/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/patologia , Hormônios/farmacologia , Humanos , Fosforilação/efeitos dos fármacos , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/patologia , Ratos , Transdução de Sinais/efeitos dos fármacos , Somatostatina/farmacologia , Somatotrofos/efeitos dos fármacos , Somatotrofos/metabolismo , Células Tumorais Cultivadas
13.
Braz J Med Biol Res ; 51(9): e7427, 2018 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-29947650

RESUMO

Genetic and functional aberrations of guanine nucleotide-binding protein, alpha stimulating (GNAS), aryl hydrocarbon receptor interacting protein (AIP), and pituitary tumor transforming gene (PTTG) are among the most prominent events in pituitary tumorigenesis. A cohort of Brazilian patients with somatotropinomas (n=41) and non-functioning pituitary adenomas (NFPA, n=21) from a single tertiary-referral center were evaluated for GNAS and AIP mutations and gene expression of AIP and PTTG. Results were compared to the clinical and biological (Ki67 and p53 expression) characteristics of tumors and their response to therapy, if applicable. Genetic analysis revealed that 27% of somatotropinomas and 4.8% of NFPA harbored GNAS mutations (P=0.05). However, no differences were observed in clinical characteristics, tumor extension, response to somatostatin analog therapy, hormonal/surgical remission rates, Ki67 index, and p53 expression between mutated and non-mutated somatotropinomas patients. PTTG overexpression (RQ mean=10.6, min=4.39, max=11.9) and AIP underexpression (RQ mean=0.56, min=0.46-max=0.92) were found in virtually all cases without a statistically significant relationship with clinical and biological tumor features. No patients exhibited somatic or germline pathogenic AIP mutations. In conclusion, mutations in GNAS and abnormal PTTG and AIP expression had no impact on tumor features and treatment outcomes in this cohort. Our data support some previous studies and point to the need for further investigations, probably involving epigenetic and transcriptome analysis, to improve our understanding of pituitary tumor behavior.


Assuntos
Adenoma/genética , Mutação em Linhagem Germinativa/genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Neoplasias Hipofisárias/genética , Adenoma/patologia , Adulto , Brasil , Carcinogênese , Transformação Celular Neoplásica , Estudos de Coortes , DNA de Neoplasias , Feminino , Marcadores Genéticos , Adenoma Hipofisário Secretor de Hormônio do Crescimento/patologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Pessoa de Meia-Idade , Hipófise/patologia , Neoplasias Hipofisárias/patologia
14.
Horm Res Paediatr ; 90(3): 196-202, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29953972

RESUMO

BACKGROUND: Somatotropinomas are rare in childhood and frequently associated with genetic mutations. AIP mutations are found in 20-25% cases and cause aggressive somatotropinomas, often resistant to somatostatin analogues. AIMS: To assess responses to multimodal therapy including pegvisomant in 2 children with sporadic somatotropinomas due to AIP mutations. CASE DESCRIPTION: We report 2 children, a boy aged 13 and a girl aged 10, with rapid growth, visual impairment, and growth hormone hypersecretion. Magnetic resonance imaging confirmed a pituitary macroadenoma with parasellar extension in both. Despite multiple surgical attempts to debulk tumour mass, residual tumour persisted. Genetic analysis showed two different AIP mutations (patient 1: c.562delC [p.Arg188Glyfs*8]; patient 2: c.140_ 163del24 [p.Gly47_Arg54del8]). They were initially treated with a long-acting somatostatin analogue (octreotide LAR 30 mg/month) and cabergoline as a dopamine agonist, with the later addition of pegvisomant titrated up to 20 mg/day and with radiotherapy for long-term control. Somatostatin analogue was ceased due to patient intolerance and lack of control. Patient 1 had normalization of insulin-like growth factor-1 (IGF-1) after 5 months of combined therapy with pegvisomant and cabergoline. For patient 2, normalization of IGF-1 was achieved after 2 months of cabergoline and pegvisomant. CONCLUSION: AIP-associated tumours can be resistant to management with somatostatin analogues. Pegvisomant can safely be used, to normalize IGF-1 levels and help control disease.


Assuntos
Adenoma/tratamento farmacológico , Adenoma/genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Hormônio do Crescimento Humano/análogos & derivados , Peptídeos e Proteínas de Sinalização Intracelular/genética , Acromegalia/diagnóstico , Acromegalia/tratamento farmacológico , Acromegalia/genética , Acromegalia/metabolismo , Adenoma/diagnóstico , Adenoma/metabolismo , Adolescente , Criança , Feminino , Gráficos de Crescimento , Adenoma Hipofisário Secretor de Hormônio do Crescimento/diagnóstico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/metabolismo , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Imagem por Ressonância Magnética , Masculino
15.
Sci China Life Sci ; 61(8): 893-901, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29951953

RESUMO

Currently, the primary therapeutic strategy for most growth hormone-producing pituitary adenomas (GHPA) is surgery. Due to the invasiveness of GHPA, high recurrence has limited the benefit of complete adenoma removal surgery. Epidermal growth factor-like domain 7 (EGFL7) is a secreted factor implicated in tumor angiogenesis, growth, invasiveness and metastasis in GHPA. Herein, we observed that the expression level of EGFL7 and p-EGFR in invasive GHPA was much higher than that of non-invasive GHPA. The overexpression of EGFL7 was positively correlated with activation of EGFR (p-EGFR). Noticeably, EGFL7 knockdown significantly inhibited activation of EGFR signaling cascades, including p-ERGR, p-AKT and p-ERK. Further studies showed that EGFL7 knockdown or pharmacological inhibition of EGFR-pathway, using EGFR inhibitor Tyrphostin AG-1478, significantly suppressed migration and invasion of GH3 and GT1-1 cells. In summary, our findings suggest that EGFL7 is a key factor for regulation of EGFR signaling pathway and plays an important role in migration and invasion of invasive GHPA.


Assuntos
Adenoma/metabolismo , Movimento Celular , Fatores de Crescimento Endotelial/metabolismo , Receptores ErbB/metabolismo , Adenoma Hipofisário Secretor de Hormônio do Crescimento/metabolismo , Adenoma/genética , Adenoma/patologia , Animais , Linhagem Celular Tumoral , Fatores de Crescimento Endotelial/genética , Inibidores Enzimáticos/farmacologia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/patologia , Humanos , Camundongos , Invasividade Neoplásica , Quinazolinas/farmacologia , Interferência de RNA , Ratos , Transdução de Sinais/efeitos dos fármacos , Tirfostinas/farmacologia
16.
Endocrinology ; 159(8): 2953-2965, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29931263

RESUMO

The cytoskeletal protein filamin A (FLNA) has been suggested to play an important role in the responsiveness of GH-secreting pituitary tumors to somatostatin receptor subtype 2 (SSTR2) agonists by regulating SSTR2 expression and signaling. However, the underlying mechanisms are unknown. In this study, we use fast multicolor single-molecule microscopy to image individual SSTR2 and FLNA molecules at the surface of living cells with unprecedented spatiotemporal resolution. We find that SSTR2 and FLNA undergo transient interactions, which occur preferentially along actin fibers and contribute to restraining SSTR2 diffusion. Agonist stimulation increases the localization of SSTR2 along actin fibers and, subsequently, SSTR2 clustering and recruitment to clathrin-coated pits (CCPs). Interfering with FLNA-SSTR2 binding with a dominant-negative FLNA fragment increases SSTR2 mobility, hampers the formation and alignment of SSTR2 clusters along actin fibers, and impairs both SSTR2 recruitment to CCPs and SSTR2 internalization. These findings indicate that dynamic SSTR2-FLNA interactions critically control the nanoscale localization of SSTR2 at the plasma membrane and are required for coupling SSTR2 clustering to internalization. These mechanisms explain the critical role of FLNA in the control of SSTR2 expression and signaling and suggest the possibility of targeting SSTR2-FLNA interactions for the therapy of pharmacologically resistant GH-secreting pituitary tumors.


Assuntos
Filaminas/metabolismo , Regulação Neoplásica da Expressão Gênica , Receptores de Somatostatina/metabolismo , Somatostatina/análogos & derivados , Citoesqueleto de Actina/metabolismo , Adenoma/tratamento farmacológico , Adenoma/genética , Adenoma/metabolismo , Animais , Células CHO , Invaginações Revestidas da Membrana Celular/metabolismo , Cricetulus , Filaminas/ultraestrutura , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/metabolismo , Células HEK293 , Humanos , Ligação Proteica , Transporte Proteico , Receptores de Somatostatina/agonistas , Receptores de Somatostatina/ultraestrutura , Imagem Individual de Molécula
17.
Hum Mol Genet ; 27(15): 2604-2613, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29726992

RESUMO

Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene cause mostly somatotropinomas and/or prolactinomas in a subset of familial isolated pituitary adenomas (FIPA). AIP has been shown to interact with phosphodiesterases (PDEs) and G proteins, suggesting a link to the cyclic AMP (cAMP)-dependent protein kinase (PKA) pathway. Upregulation of PKA is seen in sporadic somatotropinomas that carry GNAS mutations, and those in Carney complex that are due to PRKAR1A mutations. To elucidate the mechanism of AIP-dependent pituitary tumorigenesis, we studied potential functional and physical interactions of AIP with PKA's main subunits PRKAR1A (R1α) and PRKACA (Cα). We found that AIP physically interacts with both R1α and Cα; this interaction is enhanced when all three components are present, but maintained during Cα-R1α dissociation by PKA activation, indicating that AIP binds Cα/R1α both in complex and separately. The interaction between AIP and R1α/Cα is reduced when the frequent AIP pathogenic mutation p.R304* is present. AIP protein levels are regulated both by translation and the ubiquitin/proteasome pathway and Cα stabilizes both AIP and R1α protein levels. AIP reduction by siRNA leads to an increase of PKA activity, which is disproportionately enhanced during PDE4-inhibition. We show that AIP interacts with the PKA pathway on multiple levels, including a physical interaction with both the main regulatory (R1α) and catalytic (Cα) PKA subunits and a functional interaction with PDE4-dependent PKA activation. These findings provide novel insights on the mechanisms of AIP-dependent pituitary tumorigenesis.


Assuntos
Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/metabolismo , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/metabolismo , Animais , Linhagem Celular Tumoral , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/genética , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Inibidores da Fosfodiesterase 4/farmacologia , Estabilidade Proteica , Ratos , Rolipram/farmacologia
18.
Mol Cell Endocrinol ; 476: 103-109, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-29729370

RESUMO

Type 4 phosphodiesterases (PDE4s) of the large PDE enzyme superfamily have unique specificity for cAMP and may, therefore, be relevant for somatotroph tumorigenesis. Somatotroph adenomas typically overexpress PDEs probably as part of a compensatory mechanism to reduce cAMP levels. The rat PDE4A5 isoform (human homolog PDE4A4) interacts with the AIP protein, coded by a tumour suppressor gene mutated in a subgroup of familial isolated pituitary adenomas (FIPAs). PDE4A8 is the closest related isoform of PDE4A4. We aimed to evaluate the expression of both PDE4A4 and PDE4A8 in GH cells of AIP-mutated adenomas and compare their expression with that in GH cells from sporadic AIP-mutation negative GH-secreting adenomas, where we had shown previously that both PDE4A4 and PDE4A8 isoforms had been over-expressed. Confocal immunofluorescence analysis showed that both PDE4A8 and PDE4A4 had lower expression in AIP-mutated somatotropinoma samples compared to sporadic GH-secreting tumours (P < 0.0001 for both). Based on the association of low PDE4A4 and PDE4A8 expression with germline AIP-mutations positive samples we suggest that lack of AIP hinders the upregulation of PDE4A8 and PDE4A4 protein seen in sporadic somatotrophinomas. These data point to a unique disturbance of the cAMP-PDE pathway in AIP-mutation positive adenomas, which may help to explain their well-described poor response to somatostatin analogues.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Adenoma Hipofisário Secretor de Hormônio do Crescimento/enzimologia , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação/genética , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
19.
Int J Dev Neurosci ; 67: 46-50, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29604339

RESUMO

Aggressive growth hormone-secreting pituitary adenomas (GHPAs) represent an important clinical problem in patients with acromegaly. Surgical therapy, although often the mainstay of treatment for GHPAs, is less effective in aggressive GHPAs due to their invasive and destructive growth patterns, and their proclivity for infrasellar invasion. LncRNAs are important players in cancer development and emerging in various fundamental biological processes. In the present study, qRT-PCR was performed to examine the expression of lncRNA H19 and MALAT-1 in invasive and non-invasive GHPAs. Our results revealed that the expression of lncRNA H19 was remarkably higher in invasive GHPAs, however, there was no significant differences between the expression of lncRNA MALAT-1 in invasive GHPAs and non-invasive GHPAs, suggesting that lncRNA H19 may play an important role in GHPA invasion. LncRNA H19 might be a target for the study of GHPAs invasion, and a potential index for the diagnosis or prognosis of GHPAs.


Assuntos
Adenoma/genética , Regulação Neoplásica da Expressão Gênica/fisiologia , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , RNA Longo não Codificante/genética , Adenoma/diagnóstico por imagem , Adenoma/metabolismo , Adulto , Feminino , Hormônio do Crescimento/metabolismo , Adenoma Hipofisário Secretor de Hormônio do Crescimento/diagnóstico por imagem , Adenoma Hipofisário Secretor de Hormônio do Crescimento/metabolismo , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , RNA Longo não Codificante/metabolismo , RNA Mensageiro/metabolismo , Estudos Retrospectivos
20.
Pituitary ; 21(4): 355-361, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29564694

RESUMO

Sirtuins 1-7 (SIRT) are a highly conserved family of histone deacetylases involved in the regulation of longevity that have a considerable impact in transcription, DNA repair regulation, telomeric stability, cell senescence and apoptosis. In the present study, SIRT1-7 mRNA levels were evaluated in 37 somatotropinomas and 31 nonfunctioning pituitary adenomas (NFPAs) using qPCR and relation to tumor size, invasiveness and Ki-67 proliferative index was made. Overexpression of SIRT1 was observed in 86.5% of somatotropinomas versus 41.9% of NFPAs (P < 0.01). SIRT3 was more underexpressed in NFPAs than somatotropinomas (77.4 and 40.5%, respectively, P < 0.01) as well as SIRT4 and SIRT7. Despite the lack of association between sirtuins and invasiveness or Ki-67 index, SIRT1 and SIRT3 expressions were related to tumor size. Mean of the largest diameter was smaller in adenomas with SIRT1 overexpression than with normal expression (P < 0.01) and SIRT3 underexpression was associated with larger tumors (P < 0.01). In conclusion, a pronounced difference in sirtuins expression was identified between pituitary adenomas, suggesting that these genes are potential markers of pituitary adenomas and could be employed in the characterization of somatotropinomas and NFPAs. The role of sirtuins in pathogenesis of pituitary tumors merits further investigation and possibly will provide new molecular insight about their progression.


Assuntos
Adenoma/metabolismo , Neoplasias Hipofisárias/metabolismo , Sirtuínas/metabolismo , Adenoma/genética , Adenoma/patologia , Adulto , Feminino , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/metabolismo , Adenoma Hipofisário Secretor de Hormônio do Crescimento/patologia , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/patologia , Sirtuína 1/genética , Sirtuína 1/metabolismo , Sirtuína 2/genética , Sirtuína 2/metabolismo , Sirtuína 3/genética , Sirtuína 3/metabolismo , Sirtuínas/genética
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