Article

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: Aryl hydrocarbon Receptor (AHR) pathway has a key-role in cellular detoxification mechanisms and seems implicated in tumorigenesis. Moreover, polymorphisms and mutations of AHR gene have been associated with several human and animal tumours. Although AHR has been found differently expressed in pituitary adenomas, AHR gene mutation status has never been investigated in acromegalic patients. In this study we evaluated patients with apparently sporadic GH-secreting pituitary adenoma for AHR gene variants. 70 patients with sporadic GH-secreting pituitary adenoma (M=27, age 59.1±1.6 years) and 157 sex- and age-matched controls were enrolled in the study. In all patients and controls, the exons 1, 2, 3, 5 and 10 of AHR gene were evaluated for nucleotide variants by sequencing analysis. The rs2066853 polymorphism was identified in the exon 10 of 18/70 acromegalic patients and 9/157 healthy subjects (25.7 vs. 5.7%, χ(2) 18.98 p <0.0001), in homozygosis in one patient and in heterozygosis in the other 17 and in the 9 healthy subjects. Moreover, a heterozygous rs4986826 variant in exon 10 was identified in a patient with heterozygous rs2066853 polymorphism, and in the patient with homozygous rs2066853 variant. This second polymorphism was not detected in the control group. Patients with rs2066853 polymorphism showed increased IGF-1 ULN (p <0.05) and prevalence of cavernous sinus invasion (p <0.05), thyroid (p 0.02), bladder (p 0.0001) or lymphohematopoietic (p <0.05) tumours. AHR gene rs2066853 polymorphism is significantly more frequent in acromegalic patients than in healthy subjects, regardless of gender, pituitary tumour size, age at diagnosis and prevalence of colonic tumours and is associated with increased disease aggresivity. Moreover, the rs4986826 variant was detected in few patients with rs2066853 polymorphism, but its role is to be cleared. This article is protected by copyright. All rights reserved.
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    Oncogene 03/2014; · 8.56 Impact Factor

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