•Here we investigated the role of miR-23b and miR-130b in pituitary carcinogenesis.•miR-23b and miR-130b are reduced in pituitary adenomas of different histotype.•miR-23b and miR-130b target HMGA2 ...and cyclin A2 (CCNA2) genes, respectively.•HMGA2 and cyclin A2 (CCNA2) play a critical role in pituitary tumorigenesis.
MicroRNA (miRNA) deregulation plays a critical role in tumorigenesis. miR-23b and miR-130b are induced by thyrotropin in thyroid cells in a cAMP-dependent manner.
The aim of our work has been to investigate the possible role of miR-23b and miR-130b in pituitary tumorigenesis. We have analyzed their expression in a panel of pituitary adenomas (PAs) including GH and NFPA adenomas.
We report that miR-23b and miR-130b are drastically reduced in GH, gonadotroph and NFPA adenomas in comparison with normal pituitary gland. Interestingly, the overexpression of miR-23b and miR-130b inhibits cell proliferation arresting the cells in the G1 and G2 phase of the cell cycle, respectively. Moreover, we demonstrate that miR-23b and miR-130b target HMGA2 and cyclin A2 (CCNA2) genes, respectively. Finally, downregulation of miR-23b and miR-130b expression is associated with increased levels of their respective targets in human PAs.
These findings suggest that miR-23b and miR-130b downregulation may contribute to pituitary tumorigenesis.
Acromegaly reportedly carries an increased risk of malignant and benign thyroid tumors, with a prevalence of thyroid cancer of around 3-7%. Germline mutations in the aryl-hydrocarbon receptor (AHR) ...interacting protein (AIP) have been identified in familial forms of acromegaly. The molecular and endocrine relationships between follicular thyroid growth and GH-secreting pituitary adenoma have yet to be fully established. Our aim was to study the prevalence of differentiated thyroid cancer (DTC) in acromegaly, focusing on the role of genetic events responsible for the onset of thyroid cancer.
Germline mutations in the AIP gene were assessed in all patients; BRAF and H-N-K RAS status was analyzed by direct sequencing in thyroid specimens, while immunohistochemistry was used to analyze the protein expression of AIP and AHR. A set of PTCs unrelated to acromegaly was also studied.
12 DTCs (10 papillary and 2 follicular carcinomas) were identified in a cohort of 113 acromegalic patients. No differences in GH/IGF-1 levels or disease activity emerged between patients with and without DTC, but the former were older and more often female. BRAF V600E was found in 70% of the papillary thyroid cancers; there were no RAS mutations. AIP protein expression was similar in neoplastic and normal cells, while AHR protein was expressed more in PTCs carrying BRAF mutations than in normal tissue, irrespective of acromegaly status.
The prevalence of DTC in acromegaly is around 11% and endocrinologists should bear this in mind, especially when examining elderly female patients with uninodular goiter. The DTC risk does not seem to correlate with GH/IGF-1 levels, while it may be associated with BRAF mutations and AHR over-expression. Genetic or epigenetic events probably play a part in promoting thyroid carcinoma.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Germline aryl hydrocarbon receptor interacting protein (AIP) gene mutations confer a predisposition to pituitary adenoma (PA), predominantly GH-secreting (GH-PA). As recent data suggest a role for ...AIP in the pathogenesis of sporadic GH-PA and their response to somatostatin analogues (SSA), the expression of AIP and its partner, aryl hydrocarbon receptor (AHR), was determined by semiquantitative immunohistochemistry scoring in 62 sporadic GH-PA (37 treated with SSA preoperatively). The influence of Gsp status was studied in a subset of tumours (n=39, 14 Gsp+) and six GH-PA were available for primary cultures. AIP and AHR were detected in most cases, with a positive correlation between AIP and cytoplasmic AHR (P=0.012). Low AIP expression was significantly more frequent in untreated vs SSA-treated tumours (44.0 vs 20.5%, P=0.016). AHR expression or localisation did not differ between the two groups. Similarly, in vitro octreotide induced a median twofold increase in AIP expression (range 1.2–13.9, P=0.027) in GH-PA. In SSA-treated tumours, the AIP score was significantly higher in the presence of preoperative IGF1 decrease or tumour shrinkage (P=0.008 and P=0.014 respectively). In untreated tumours, low AIP expression was significantly associated with invasiveness (P=0.028) and suprasellar extension (P=0.019). The only effect of Gsp status was a significantly lower nuclear AHR score in Gsp+ vs Gsp− tumours (P=0.025), irrespective of SSA. In conclusion, AIP is involved in the aggressiveness of sporadic GH-PA, regardless of Gsp status, and AIP up-regulation in SSA-treated tumours is associated with a better preoperative response, with no clear role for AHR.
To search for a possible role of Peroxisome Proliferator-Activated Receptor α (PPARα), a molecular partner of the Aryl hydrocarbon receptor Interacting Protein (AIP), in somatotropinomas.
Tumours ...from 51 acromegalic patients were characterized for PPARα and AIP expression by immunohistochemistry (IHC) and/or Real Time RT-PCR. Data were analysed according to tumour characteristics and pre-operative treatment with somatostatin analogues (SSA). The effects of fenofibrate were studied in GH3 cells in vitro.
PPARα was expressed in most somatotropinomas. A modest relationship was found between PPARα and AIP expression, both being significantly higher in the presence of pre-operative SSA. However, only AIP expression was influenced by the response to treatment. Dual effects of fenofibrate were observed in GH3 cells, consisting of cell growth inhibition and an increase in GH secretion inhibited by octreotide.
PPARα is a new player in somatotropinomas. Potential interactions between PPARα agonists and SSA may deserve further investigation.
•PPARα, a molecular partner of AIP, is commonly expressed in somatotropinomas.•PPARα is unlikely to play a major role in AIP-related somatotroph tumorigenesis.•Somatostatin analogues (SSA) increase PPARα expression in somatotroph tumours.•Fenofibrate has differential effects on GH3 cell growth and hormone secretion.•Potential interactions between PPRAα agonists and SSA deserve further investigation.
PURPOSE: To search for a possible role of Peroxisome Proliferator-Activated Receptor alpha (PPARalpha), a molecular partner of the Aryl hydrocarbon receptor Interacting Protein (AIP), in ...somatotropinomas. METHODS: Tumours from 51 acromegalic patients were characterized for PPARalpha and AIP expression by immunohistochemistry (IHC) and/or Real Time RT-PCR. Data were analysed according to tumour characteristics and pre-operative treatment with somatostatin analogues (SSA). The effects of fenofibrate were studied in GH3 cells in vitro. RESULTS: PPARalpha was expressed in most somatotropinomas. A modest relationship was found between PPARalpha and AIP expression, both being significantly higher in the presence of pre-operative SSA. However, only AIP expression was influenced by the response to treatment. Dual effects of fenofibrate were observed in GH3 cells, consisting of cell growth inhibition and an increase in GH secretion inhibited by octreotide. CONCLUSIONS: PPARalpha is a new player in somatotropinomas. Potential interactions between PPARalpha agonists and SSA may deserve further investigation.
AEgIS (Antimatter Experiment: Gravity, Interferometry, Spectroscopy) is an experiment that aims to perform the first direct measurement of the gravitational acceleration g of antihydrogen in the ...Earth’s field. A cold antihydrogen beam will be produced by charge exchange reaction between cold antiprotons and positronium excited in Rydberg states. Rydberg positronium (with quantum number
n
between 20 and 30) will be produced by a two steps laser excitation. The antihydrogen beam, after being accelerated by Stark effect, will fly through the gratings of a moiré deflectometer. The deflection of the horizontal beam due to its free fall will be measured by a position sensitive detector. It is estimated that the detection of about 10
3
antihydrogen atoms is required to determine the gravitational acceleration with a precision of 1%. In this report an overview of the AEgIS experiment is presented and its current status is described. Details on the production of slow positronium and its excitation with lasers are discussed.
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