Steroidogenic Factor 1 Overexpression and Gene Amplification Are More Frequent in Adrenocortical Tumors from Children than from Adults

Almeida, Madson Q.; Soares, Iberê C.; Ribeiro, Tatiane Bomfim; Fragoso, Maria Candida Barisson Villares; Marins, Lidiane V.; Wakamatsu, Alda; Réssio, Rodrigo Albergaria; Nishi, Mirian Yumie; Jorge, Alexander A L; Lerário, Antônio Marcondes; Alves, Venâncio Avancini Ferreira; Mendonca, Berenice B.; Latrônico, Ana Claudia

doi:10.1210/jc.2009-2040

Cited by 74 publications

(73 citation statements)

References 23 publications

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“…Namely, those animals lacked steroidogenic tissues, such as adrenal glands and gonads [9][10][11][12] . By contrast, the overexpression of Ad4BP/SF-1 induced enlargement/ectopic formation and tumorigenesis of the adrenal cortex [13][14][15][16] . Taken together, these studies strongly suggested that Ad4BP/SF-1 is involved in the regulation of cellular proliferation and maintenance.…”

mentioning

confidence: 88%

Glycolytic genes are targets of the nuclear receptor Ad4BP/SF-1

et al. 2014

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Genetic deficiencies in transcription factors can lead to the loss of certain types of cells and tissue. The steroidogenic tissue-specific nuclear receptor Ad4BP/SF-1 (NR5A1) is one such gene, because mice in which this gene is disrupted fail to develop the adrenal gland and gonads. However, the specific role of Ad4BP/SF-1 in these biological events remains unclear. Here we use chromatin immunoprecipitation sequencing to show that nearly all genes in the glycolytic pathway are regulated by Ad4BP/SF-1. Suppression of Ad4BP/SF-1 by small interfering RNA reduces production of the energy carriers ATP and nicotinamide adenine dinucleotide phosphate, as well as lowers expression of genes involved in glucose metabolism. Together, these observations may explain tissue dysgenesis as a result of Ad4BP/SF-1 gene disruption in vivo. Considering the function of estrogen-related receptor a, the present study raises the possibility that certain types of nuclear receptors regulate sets of genes involved in metabolic pathways to generate energy carriers.

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mentioning

confidence: 88%

Glycolytic genes are targets of the nuclear receptor Ad4BP/SF-1

et al. 2014

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“…Apart from transcriptome analyses, one of the most common methods to screen a large number of samples is tissue microarray: it has been widely used for immunohistochemistry studies on adrenocortical tumours [21,34,51,52,67,69,80,168].…”

Section: Molecular Research Methodsmentioning

confidence: 99%

“…some gain or amplification at 9q33 [65][66][67]. SF-1 also shows prognostic information: higher expression correlates with more advanced tumour stage, poorer clinical outcome, and shorter overall survival [68,69].…”

Section: Prace Poglądowementioning

confidence: 99%

Szlaki molekularne w raku kory nadnercza — od wiedzy o sygnalizacji komórkowej do metod diagnostyki i leczenia

Szyszka

Grossman

Díaz‐Cano

et al. 2015

Endokrynologia Polska

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Adrenocortical carcinoma is associated with a low cure rate and a high recurrence rate. The prognosis is poor, and at diagnosis 30-40% of cases are already metastatic. The current therapeutic options (surgical resection, followed by adjuvant mitotane treatment +/-chemotherapy) are limited, and the results remain unsatisfactory. Key molecular events that contribute to formation of adrenocortical cancer are IGF2 overexpression, TP53-inactivating mutations, and constitutive activation of the Wnt/b-catenin signalling pathway via activating mutations of the b-catenin gene. The underlying genetic causes of inherited tumour syndromes have provided insights into molecular pathogenesis. The increased occurrence of adrenocortical tumours in Li-Fraumeni and Beckwith-Wiedemann syndromes, and Carney complex, has highlighted the roles of specific susceptibility genes: TP53, IGF2, and PRKAR1A, respectively. Further studies have confirmed that these genes are also involved in sporadic tumour cases. Crucially, transcriptome-wide studies have determined the differences between malignant and benign adrenocortical tumours, providing potential diagnostic tools. In conclusion, enhancing our understanding of the molecular events of adrenocortical tumourigenesis, especially with regard to the signalling pathways that may be disrupted, will greatly contribute to improving a range of available diagnostic, prognostic, and treatment approaches. StreszczenieRak kory nadnercza charakteryzuje się niską wyleczalnością i wysokim ryzykiem nawrotu. Rokowanie jest złe, a 30-40% przypadków okazuje się być przerzutami już przy diagnozie. Obecnie dostępne opcje terapeutyczne (chirurgiczna resekcja z następującym adjuwantowym leczeniem mitotanem, czasem połączonym z chemoterapią) są ograniczone, a ich wyniki są mało satysfakcjonujące. Kluczowe zmiany molekularne przyczyniające się to rozwoju raka kory nadnercza to nadekspresja IGF2, mutacje inaktywujące TP53 oraz konstytutywna aktywacja szklaku sygnałowego Wnt/b-katenina poprzez mutacje aktywujące gen b-kateniny. Genetyczne przyczyny leżące u podstaw dziedzicznych zespołów nowotworowych dostarczyły wgląd w ich patogenezę molekularną. Zespoły: Li-Fraumeni, Beckwitha-Wiedemanna oraz Carneya, charakteryzujące się zwiększoną predyspozycją do nowotworów kory nadnercza, uwidoczniły określone geny podatności, odpowiednio: TP53, IGF2 oraz PRKAR1A. Dalsze badania potwierdziły udział tych genów także w nowotworach sporadycznych. Co istotne, badania transkryptomu wykazały istotne różnice między nowotworami złośli-wymi i łagodnymi, dostarczając potencjalnych opcji diagnostycznych. Podsumowując, wzbogacenie wiedzy na temat molekularnych podstaw, a szczególnie szlaków sygnałowych, które mogą być zaburzone w procesie nowotworzenia w obrębie kory nadnercza znacznie przyczyni się poprawieniu możliwości diagnostycznych, rokowniczych oraz leczniczych. (Endokrynol Pol 2016; 67 (4): 427-440) Słowa kluczowe: rak kory nadnerczy; nowotwory kory nadnercza; patologia molekularna; szlaki transdukcji sygnałów; zespoły n...

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“…In our study, the RNAseP gene was co-amplified with the AHI1 gene and served as an internal standard (two copies present in a subject with or without increase in the AHI1 gene). The formula of 'intermediate' measurement from manufacturer's protocol (Applied Biosystems pre-design TaqMan copy number assays kit) and other studies was used to analyze the estimated copy number (16,17,18). It is equal to 2 !2 KDDC t and represents the transformation of the relative abundance of the gene of interest in a given sample (DDC t ) from the 'C t ' scale to copy number scale.…”

Section: Verification Of Copy Numbers By Qrt-pcrmentioning

confidence: 99%

Association of copy number variation in the AHI1 gene with risk of obesity in the Chinese population

Huang

Teng²,

Wang³

et al. 2012

European Journal of Endocrinology

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ObjectiveThe prevalence of obesity has increased dramatically over the past decade. Gene copy number variants (CNVs) have been recognized as a hereditable source of susceptibility in human complex diseases including obesity. Recent studies have shown that Abelson helper integration site 1 (Ahi1) gene has a significant contribution in the homeostasis regulation in mouse models of obesity. A study was therefore carried out to investigate whether CNVs inAHI1gene contribute to human obesity.Subjects and methodsWe analyzed samples from 70 Chinese overweight adults and 74 healthy controls for DNA copy number change using the Affymetrix single-nucleotide polymorphism (SNP) 6.0 array. Validation of CNVs ofAHI1was achieved by real-time PCR using the ΔΔCtmethod.ResultsCopy number gain analysis revealed significant gains (P=0.0017) ofAHI1gene copy number in 17 of 70 (24.3%) samples but only four of 74 (5.4%) controls overall. Then we studied the frequency distribution of CNVs inAHI1gene according to body mass index (BMI) grade. Five out of 28 (18.5%) at-risk obese, six out of 26 (26.9%) moderate obese, and six out of 17 (29.4%) severe obese subjects studied showed increasedAHI1gene copy number.ConclusionsThe result suggested that there was a significant linear trend for increasingAHI1gene copy number frequencies with increasing BMI.

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Steroidogenic Factor 1 Overexpression and Gene Amplification Are More Frequent in Adrenocortical Tumors from Children than from Adults

Abstract: We demonstrated a higher frequency of SF-1 overexpression and gene amplification in pediatric than in adult adrenocortical tumors, suggesting an important role of SF-1 in pediatric adrenocortical tumorigenesis.

Cited by 74 publications

References 23 publications

Glycolytic genes are targets of the nuclear receptor Ad4BP/SF-1

Glycolytic genes are targets of the nuclear receptor Ad4BP/SF-1

Szlaki molekularne w raku kory nadnercza — od wiedzy o sygnalizacji komórkowej do metod diagnostyki i leczenia

Association of copy number variation in the AHI1 gene with risk of obesity in the Chinese population

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