SFEBES2019 ORAL POSTER PRESENTATIONS Neuroendocrinology, Pituitary and Neoplasia (4 abstracts)
Transcriptomic analyses reveal deregulation of focal adhesion pathway in Aip KO mice and AIP mutation positive human tumours
Mark Bollington 1 , Anisha Mistry 1 , Antonia Solomou 1 , Sayka Barry 1 , Federica Begalli 1 , Maria Vignola 1, , Chung Thong Lim 1 , Mária Hérincs 1 , Federico Roncaroli 3 , Carles Gaston-Massuet 1 & Márta Korbonits 1
1Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, UK; 2King's College London, London, UK; 3University of Manchester, Manchester, UK
Introduction: AIP mutations are responsible for 15-30% of cases of familial isolated pituitary adenomas. The pathophysiology that drives this AIP-related pituitary tumorigenesis is not fully understood. We developed a pituitary-specific Aip knockout (KO) mouse model, which mostly recapitulates the human phenotype.
Aims: To performed comparative gene expression analysis of Aip-KO mouse pituitary tumours and AIP mutation positive human pituitary tumours in order to identify the genes and signalling pathways involved in Aip-related pituitary adenoma progression.
Methods: RT-qPCR was performed to confirm the expression of the selected candidate genes at the mRNA level. Immunofluorescence immunohistochemistry on mouse pituitary sections and immunoblotting for Aip-KO embryonic fibroblast were used to validate the changes at the protein level.
Results: Comparative gene expression analysis of Aip-KO mouse RNA-seq and human AIP mutation positive microarray gene expression data identified 50 common genes. 11 of 50 genes were statistically significantly differentially expressed with the same direction of change. Pathway analysis of these genes revealed that FAK pathway is one of the significant altered pathways. Five genes (Actg1, Col6a1, Itgb6, Lamc2 and Cdh3) from this pathway were selected for further validation. As well as a separate gene (Cdc42) that had been implicated in our human data and rat cell-line. Our data suggests that the development of Aip-related pituitary adenomas may be mediated by the altered expression of these genes. We validated these data at the protein level with immunofluorescence using Aip-KO embryonic fibroblast and immunofluorescence immunohistochemistry in pituitary-specific Aip-KO pituitary. ITGB6 and LAMC2 were downregulated in the Aip-KO fibroblasts and mouse model.
Conclusion: ITGB6 and LAMC2 are important proteins for focal adhesion, the downregulation of ITGB6 and LAMC2 may lead to dysfunction of this pathway, which may lead to the pituitary tumorigenesis associated with AIP deficiency.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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