Differential expression of neurogenins and NeuroD1 in human pituitary tumours

Fratticci, Amato; Grieco, Fabio Arturo; Spilioti, Cristina; Giangaspero, Felice; Ventura, Laura; Esposito, Vincenzo; Piccirilli, Manolo; Santoro, Antonio; Gulino, Alberto; Cantore, Giampaolo; Alesse, Edoardo; Jaffrain-Rea, Marie Lise

doi:10.1677/joe-07-0020

Cited by 18 publications

(15 citation statements)

References 40 publications

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“…Constitutive expression of AHR and ARNT has been shown in the rat hypothalamus (Korkalainen et al 2005). These data suggest a physiological role for AHR in the human hypothalamus-pituitary unit, further extending the spectrum of bHLH transcription factors expressed in the normal pituitary and PA (Jackson et al 1993, Ferretti et al 2001, Huang et al 2002, Fratticci et al 2007.…”

Section: Discussionmentioning

confidence: 52%

“…Tumours showing microscopic evidence of contamination by normal pituitary fragments were considered for immunohistochemical studies only. In addition, normal human pituitary glands were collected at autopsy in four patients who died from non-endocrine diseases and divided into frozen and formalin-fixed paraffin-embedded fragments, as previously described (Fratticci et al 2007). …”

Section: M-l Jaffrain-rea Et Al: Ahr and Aip In Pituitary Adenomasmentioning

confidence: 99%

“…in all cases. A double step immunohistochemical study was also performed as previously described (Fratticci et al 2007) to first detect cytoplasmic AIP or the pituitary hormones GH, PRL, ACTH and FSH respectively using 3-3 0 -diaminobenzidine (DAB) as a chromogen, followed by a second step for the detection of nuclear AHR (C-pAb) using Novored as a chromogen (Vector, DBA Italia), introducing a further blocking step with milk as indicated hitherto. Photographs of slides were taken using a Zeiss Axioplan 2 microscope and a Leica DFC 320 digital camera.…”

Section: Immunohistochemistrymentioning

confidence: 99%

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Expression of aryl hydrocarbon receptor (AHR) and AHR-interacting protein in pituitary adenomas: pathological and clinical implications

Jaffrain-Rea¹,

Angelini

Gargano

et al. 2009

Endocrine-Related Cancer

134

103

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3Fondazione 'Carlo Ferri' per la prevenzione e la cura dei tumori, via Edmondo Riva 42, 00015 Monterotondo, Italy AbstractGermline mutations of the aryl hydrocarbon receptor (AHR)-interacting protein (AIP) gene confer a predisposition to pituitary adenomas (PA), usually in the setting of familial isolated PA. To provide further insights into the possible role of AIP in pituitary tumour pathogenesis, the expression of AIP and AHR was determined by real-time RT-PCR and/or immunohistochemistry (IHC) in a large series of PA (nZ103), including 17 with AIP mutations (AIP mut ). Variable levels of AIP and AHR transcripts were detected in all PA, with a low AHR expression (P!0.0001 versus AIP). Cytoplasmic AIP and AHR were detected by IHC in 84.0 and 38.6% of PA respectively, and significantly correlated with each other (PZ0.006). Nuclear AHR was detected in a minority of PA (19.7%). The highest AIP expression was observed in somatotrophinomas and non-secreting (NS) PA, and multivariate analysis in somatotrophinomas showed a significantly lower AIP immunostaining in invasive versus non-invasive cases (PZ0.019). AIP expression was commonly low in other secreting PA. AIP immunostaining was abolished in a minority of AIP mut PA, with a frequent loss of cytoplasmic AHR and no evidence of nuclear AHR. In contrast, AIP overexpression in a subset of NS PA could be accompanied by nuclear AHR immunopositivity. We conclude that down-regulation of AIP and AHR may be involved in the aggressiveness of somatotrophinomas. Overall, IHC is a poorly sensitive tool for the screening of AIP mutations. Data obtained on AHR expression suggest that AHR signalling may be differentially affected according to PA phenotype.

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Section: Discussionmentioning

confidence: 52%

Section: M-l Jaffrain-rea Et Al: Ahr and Aip In Pituitary Adenomasmentioning

confidence: 99%

Section: Immunohistochemistrymentioning

confidence: 99%

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Expression of aryl hydrocarbon receptor (AHR) and AHR-interacting protein in pituitary adenomas: pathological and clinical implications

Jaffrain-Rea¹,

Angelini

Gargano

et al. 2009

Endocrine-Related Cancer

134

103

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“…In 2001, Oyama et al 62 showed that ACTH-PAs overexpress NEUROD1 and its protein product. Fratticci et al 24 confirmed this result in 2007. This mechanism, however, is not unique to functional ACTH-PAs; it has been shown that NEUROD1 expression levels are similar among ACTH-secreting tumors of both pituitary and nonpituitary origin.…”

Section: Pttgmentioning

confidence: 75%

Gene and protein expression in pituitary corticotroph adenomas: a systematic review of the literature

Seltzer¹,

Ashton²,

Scotton³

et al. 2015

FOC

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OBJECT Functional corticotroph pituitary adenomas (PAs) secrete adrenocorticotropic hormone (ACTH) and are the cause of Cushing's disease, which accounts for 70% of all cases of Cushing's syndrome. Current classification systems for PAs rely primarily on laboratory hormone findings, tumor size and morphology, invasiveness, and immunohistochemical findings. Likewise, drug development for functional ACTH-secreting PAs (ACTH-PAs) is limited and has focused largely on blocking the production or downstream effects of excess cortisol. The authors aimed to summarize the findings from previous studies that explored gene and protein expression of ACTH-PAs to prioritize potential genetic and protein targets for improved molecular diagnosis and treatment of Cushing's disease. METHODS A systematic literature review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A PubMed search of select medical subject heading (MeSH) terms was performed to identify all studies that reported gene- and protein-expression findings in ACTH-PAs from January 1, 1990, to August 24, 2014, the day the search was performed. The inclusion criteria were studies on functional ACTH-PAs compared with normal pituitary glands, on human PA tissue only, with any method of analysis, and published in the English language. Studies using anything other than resected PA tissue, those that compared other adenoma types, those without baseline expression data, or those in which any pretreatment was delivered before analysis were excluded. RESULTS The primary search returned 1371 abstracts, of which 307 were found to be relevant. Of those, 178 were selected for secondary full-text analysis. Of these, 64 articles met the inclusion criteria and an additional 4 studies were identified from outside the search for a total of 68 included studies. Compared with the normal pituitary gland, significant gene overexpression in 43 genes and 22 proteins was reported, and gene underexpression in 58 genes and 15 proteins was reported. Immunohistochemistry was used in 39 of the studies, and reverse transcriptase polymerase chain reaction was used in 26 of the studies, primarily, and as validation for 4 others. Thirteen studies used both immunohistochemistry and reverse transcriptase polymerase chain reaction. Other methods used included microarray, in situ hybridization, Northern blot analysis, and Western blot analysis. Expression of prioritized genes emphasized in multiple studies were often validated on both the gene and protein levels. Genes/proteins found to be overexpressed in ACTH-PAs relative to the normal pituitary gland included hPTTG1/securin, NEUROD1/NeuroD1 (Beta2), HSD11B2/11β-hydroxysteroid dehydrogenase 2, AKT/Akt, protein kinase B, and CCND1/cyclin D1. Candidate genes/proteins found to be underexpressed in ACTH-PAs relative to the normal pituitary gland included CDKN1B/p27Kip1, CDKN2A/p16, KISS1/kisspeptin, ACTHR/ACTH-R, and miR-493. CONCLUSIONS On the basis of the authors' systematic review, many significant gene and protein targets that may contribute to tumorigenesis, invasion, and hormone production/secretion of ACTH have been identified and validated in ACTH-PAs. Many of these potential targets have not been fully analyzed for their therapeutic and diagnostic potential but may represent candidate molecular targets for biomarker development and drug targeting. This review may help catalyze additional research efforts using modern profiling and sequencing techniques and alteration of gene expression.

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“…18 Most human pituitary adenomas are monoclonal in origin, and various transcription factors, such as PIT1, NEUROD1, GATA2, MSX1, and PTX1, may participate in the differentiation and functional expression of pituitary adenomas. [24][25][26][27][28][29] We report that FOXL2 is expressed mainly in gonadotropes of normal pituitaries, and is observed in Gn-omas and null cell adenomas, which are derived from gonadotroph (LH/FSH producing) cells. 30 Our findings suggest that FOXL2 has a role in differentiation toward gonadotropin (LHb, FSHb, aGSU)-producing cells in normal pituitaries.…”

Section: Discussionmentioning

confidence: 98%

Expression of FOXL2 in human normal pituitaries and pituitary adenomas

Egashira¹,

Takekoshi

Takei

et al. 2011

Modern Pathology

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Many transcription factors have important roles in the function and differentiation of the human pituitary adenomas. Forkhead box gene transcription factor L2, Foxl2, is expressed during mouse pituitary development and co-localizes with the expression of a-glycoprotein hormone subunit (aGSU). In addition, Foxl2 regulates expression of the aGSU gene (Cga) in cell culture. To elucidate the functional role of FOXL2 in the human pituitary, we examined the expression and localization of FOXL2 in normal human pituitaries and various types of pituitary adenomas. Human pituitary adenomas were obtained by trans-sphenoidal surgery from 67 patients. Three normal adult pituitaries were obtained from autopsies of non-endocrine cases. The localization of FOXL2 and pituitary hormones in these pituitary patients was examined by immunohistochemical staining and RT-PCR. Quantitative analysis of FOXL2 protein was performed by immunoblotting. FOXL2 was localized in the nuclei of B20% of normal pituitary cells that also co-expressed gonadotropins including follicule-stimulating hormone b (FSHb), luteinizing hormone b (LHb), and aGSU, whereas it was observed in minor proportion of thyroid-stimulating hormone (TSH)-producing cells, prolactin (PRL)-producing cells, and precursor of adrenocorticotropic hormone (ACTH)-producing cells. FOXL2 immunoreactivity was not detected in growth hormone (GH)-producing cells or S100-positive folliculo-stellate cells. In human pituitary adenomas, FOXL2 was expressed in the nuclei of the adenoma cells. FOXL2 was detected in 13 of 15 gonadotropin-subunitproducing adenoma (Gn-oma) cases and 8 of 11 null cell adenoma cases, but its incidence was reduced or not detected in the other types of adenomas. The results of this study suggest that FOXL2 contributes to the human-specific functional expression and the differentiation of gonadotroph cells and adenomas. 1 The pituitary cell types can be classified into three cell lineages: the growth hormone (GH)-prolactin (PRL)-thyroid-stimulating hormone (TSH) (GH-PRL-TSH) cell lineage, the proopiomelanocortin (precursor of adrenocorticotropic hormone, ACTH) lineage, and the gonadotropin (luteinizing hormone/follicle-stimulating hormone; LH/FSH) lineage. Several transcription factors are known to regulate pituitary development, proliferation, and the functional differentiation of these lineages. Pitx1, Pitx2, Lhx3, Lhx4, and Rpx/Hesx1 are expressed in early pituitary development, and are essential for normal pituitary organogenesis.2-6 On the other hand, late functional transcription factors, including Tpit, Gata2, Sf1, Egr1, Estrogen receptor (Esr1), and Zn-15, regulate the functional differentiation of each type of hormone-producing cell. [7][8][9][10][11][12] Forkhead factors are a class of transcription factors that are important for diverse developmental processes. Deficiencies of individual forkhead genes may result in

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Differential expression of neurogenins and NeuroD1 in human pituitary tumours

Cited by 18 publications

References 40 publications

Expression of aryl hydrocarbon receptor (AHR) and AHR-interacting protein in pituitary adenomas: pathological and clinical implications

Expression of aryl hydrocarbon receptor (AHR) and AHR-interacting protein in pituitary adenomas: pathological and clinical implications

Gene and protein expression in pituitary corticotroph adenomas: a systematic review of the literature

Expression of FOXL2 in human normal pituitaries and pituitary adenomas

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