The Expression of AIP-Related Molecules in Elucidation of Cellular Pathways in Pituitary Adenomas

Department of Medical Genetics, Genome-Scale Biology Research Program, University of Helsinki, Helsinki, Finland.
American Journal Of Pathology (Impact Factor: 4.6). 10/2009; 175(6):2501-7. DOI: 10.2353/ajpath.2009.081131
Source: PubMed

ABSTRACT Germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene predispose to the development of pituitary adenomas. Here, we characterized AIP mutation positive (AIPmut+) and AIP mutation negative (AIPmut-) pituitary adenomas by immunohistochemistry. The expressions of the AIP-related proteins aryl hydrocarbon receptor (AHR), AHR nuclear translocator (ARNT), cyclin-dependent kinase inhibitor 1B encoding p27(Kip1), and hypoxia-inducible factor 1-alpha were examined in 14 AIPmut+ and 53 AIPmut- pituitary adenomas to detect possible expression differences. In addition, the expression of CD34, an endothelial and hematopoietic stem cell marker, was analyzed. We found ARNT to be less frequently expressed in AIPmut+ pituitary adenomas (P = 0.001), suggesting that AIP regulates the ARNT levels. AIP small interfering RNA-treated HeLa, HEK293, or Aip-null mouse embryonic fibroblast cells did not show lowered expression of ARNT. Instead, in the pituitary adenoma cell line GH3, Aip silencing caused a partial reduction of Arnt and a clear increase in cell proliferation. We also observed a trend for increased expression of nuclear AHR in AIPmut+ samples, although the difference was not statistically significant (P = 0.06). The expressions of p27(Kip1), hypoxia-inducible factor 1-alpha, or CD34 did not differ between tumor types. The present study shows that the expression of ARNT protein is significantly reduced in AIPmut+ tumors. We suggest that the down-regulation of ARNT may be connected to an imbalance in AHR/ARNT complex formation arising from aberrant cAMP signaling.

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    ABSTRACT: Our aim was to explore the interactions of intercellular adhesion molecule (sICAM-1), TNF-α (tumor necrosis factor-α), interleukin-1α (IL-1α) and interleukin-6 (IL-6) with dopamine agonists in a culture of adenomatous cells from an nonfunctional macroadenoma. Materials and methods. Tissue specimen from pituitary macroadenoma removed in transsphenoidal surgery was prepared for primary culture. Cells were counted and plated at 10 5 /well into 24-well plates in a final volume of 1ml. Cabergoline in molar doses of 10 -6 , 10 -7 , 10 -8 , 10 -9 was added and the cells were incubated for 4 days. sICAM-1, TNF-α, IL-1 α, IL-6 were measured from cell-culture supernatants by ELISA kits. Results. sICAM-1, TNF-α, IL-1α and IL-6 were detected in the untreated control cultures after a 4d period. There was a negative correlation between TNFα and IL-1α (p=0.007). The levels of PRL and hGH had measurable values above those found in culture medium without tumor cells. PRL positively correlated with IL-1α (p=0.05). hGH positively correlated with cell proliferation (p=0.049). Cabergoline treatment showed that IL-6 progressively decreased with the dose, ranging from -27.41% to -76.44%. TNF-α significantly decreased (-65.90%; p<0.03) at the cabergoline 10 -7 M dose. IL-1α progressively increased with cabergoline dose, ranging from -2.53% to 345 %. sICAM-1 was significantly reduced by cabergoline at 10 -9 (-47.12 %; p= 0.045) and 10 -6 M (-59.16%; p=0.01) doses. TNF-α positively correlated with PRL (p=0.025); IL-6 positively correlated with hGH (p=0.044); sICAM-1 negatively correlated with hGH (p=0.009), TNFα (p=0.025) and IL-1α (p=0.044). Conclusions. These data support the existence of an immunoendocrine network in pituitary tumorigenesis; TNF-α, IL-6, IL-1α, sICAM-1 significantly interfered by cabergoline treatment in a dose-dependent way. However, future studies on different types of pituitary tumours are needed to confirm these findings.
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    ABSTRACT: Pituitary adenomas are benign intracranial neoplasms that can result in morbidity owing to local invasion and/or excessive or deficient hormone production. The prevalence of symptomatic pituitary adenomas is approximately 1:1,000 in the general population. The vast majority of these tumours occur sporadically and are not part of syndromic disorders. However, germline mutations in genes known to predispose individuals to familial pituitary adenomas are found in a few patients with sporadic pituitary adenomas. Mutations in AIP (encoding aryl-hydrocarbon receptor-interacting protein) are the most frequently observed germline mutations. The prevalence of these mutations in patients with sporadic pituitary adenomas is ∼4%, but can increase to 8-20% in young adults with macroadenomas or gigantism, and also in children. Germline mutations in MEN1 (encoding menin) result in multiple endocrine neoplasia type 1 and are found in very young patients with isolated sporadic pituitary adenomas, which highlights the importance of the chromosome 11q13 locus in pituitary tumorigenesis. In this Review, we describe the clinical features of patients with sporadic pituitary adenomas that are associated with AIP or MEN1 mutations, and discuss the molecular mechanisms that might be involved in pituitary adenoma tumorigenesis. We also discuss genetic screening of patients with sporadic pituitary adenomas and investigations of relatives of these patients who also have the same genetic mutations.
    Nature Reviews Endocrinology 10/2014; 11(1). DOI:10.1038/nrendo.2014.181 · 12.96 Impact Factor
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    ABSTRACT: Pituitary adenomas (PA) are common endo-crine neoplasia, generally presenting as sporadic diseases, with a multifactorial pathogenesis including somatic mutational events in cancer-related genes. However, genetic predisposition can currently be recognized in >5% of affected patients, mostly involving the Multiple Endocrine Neoplasia type 1 (MEN1) gene and the more recently identi fi ed Aryl hydrocarbon receptor Interacting Protein (AIP) gene, both being tumor-suppressor genes. Germline mutations in the AIP gene can be observed in a FIPA (Familial Isolated Pituitary Adenoma) context, but also in a minority of young patients with an apparently sporadic disease. Although the role of AIP in the pathogenesis of PA remains largely unknown, it is known to be mainly expressed by somatototrophs, with a frequent loss of expression in most AIP-mutated PA and in invasive somatotro-pinomas. The best characterized function of AIP is to stabilize the Aryl hydrocarbon Receptor, also known as the dioxin receptor, in the cytoplasm, but multiple interactions of AIP with other proteins involved in endo-crine signalling and the regulation of cell cycle and apoptosis have been reported. In this chapter, current knowledge about the possible role of AhR and additional AIP-related proteins in pituitary tumorigenesis will be analysed.
    Tumours of the Central nervous System, Vol 10, Edited by Hayat A.M., 01/2013: chapter The Role of Aryl Hydrocarbon Receptor (AHR) and AHR-Interacting Protein (AIP) in the Pathogenesis of Pituitary Adenomas: pages 189-201; Springer Science+Business Media Dordrecht 2013., ISBN: 978-94-007-5681-6

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