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Endocrine Abstracts (2013) 31 OC5.2 | DOI: 10.1530/endoabs.31.OC5.2

SFEBES2013 Oral Communications Pituitary and neoplasia (8 abstracts)

The role of microRNA miR-34a in the regulation of aryl hydrocarbon receptor interacting protein

Judit Denes 1 , Leandro Kasuki 1, , Giampaolo Trivellin 1 , Monica Gadelha 1, & Marta Korbonits 1


1Department of Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK; 2Endocrinology Unit, Clemetnino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.


Germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene predispose to early onset pituitary adenoma, with a preponderance of somatotrophinomas. Patients harbouring an AIP mutation respond poorly to somatostatin analogue (SSA) treatment. On the other hand, a subset of sporadic somatotrophinomas with no AIP mutations show low AIP protein expression and exhibit a decreased response to SSA treatment as well. microRNAs are small interfering RNAs which can regulate protein expression. miR-34a is predicted to interact with specific target sequences located within the 3′ untranslated region (3′UTR) of AIP.

RNA expression levels of AIP and miR-34a were evaluated in 31 sporadic somatotrophinoma tissues (17 invasive, 14 non-invasive) by RT-qPCR and immunohistochemistry was used to assess AIP protein expression. A luciferase reporter assay was used to examine the in silico predicted target sites of miR-34a in the 3′UTR of AIP. Deletion constructs of AIP 3′UTR were utilised to confirm the binding and regulatory function of miR-34a.

Low AIP protein expression was seen in invasive sporadic somatotrophinomas, whereas the corresponding mRNA levels were not statistically different compared to non-invasive tumours. This suggests that the expression of AIP might be regulated post-transcriptionally by miRNAs, which repress gene expression mainly by inhibiting protein translation. We observed that the expression levels of miR-34a is higher in somototrophinomas with low AIP expression. (P=0.02) Co-transfection of reporter cells with a miR-34a precursor and the luciferase-WT-AIP-3′UTR plasmid construct shows a negative effect on the luciferase expression, suggesting that miR-34a binds to the AIP-3″UTR. By using deletion mutants we have validated miR-34a predicted target sites at AIP-3″UTR.

Conclusions: We have identified and proved that miR-34a is a negative regulator of AIP protein expression and increased miR-34a expression could explain the low AIP expression and resulting tumour invasiveness and decreased SSA-responsiveness of sporadic somatotrophinomas.

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