SFEBES2022 Poster Presentations Neuroendocrinology and Pituitary (72 abstracts)
Aberrant cyclic GMP-AMP synthase stimulator of interferon genes signalling in an AIP mutant cell line
Paul Benjamin Loughrey 1,2,3 , Oniz Suleyman 3 , Federica Begalli 3 , Stephanie G Craig 1 , Steven J Hunter 2 , Darragh G McArt 1 , Jacqueline A James 1,4 , Oliver Haworth 3 , Sayka Barry 3 & Marta Korbonits 3
1Precision Medicine Centre of Excellence, Patrick G Johnston Centre for Cancer Research, Queen’s University, Belfast, United Kingdom; 2Regional Centre for Endocrinology and Diabetes, Royal Victoria Hospital, Belfast Health & Social Care Trust, Belfast, United Kingdom; 3Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom; 4Regional Molecular Diagnostic Service, Health Sciences Building, Belfast Health and Social Care Trust, Belfast, United Kingdom
Background: The cyclic GMP-AMP synthase stimulator of interferon genes (cGAS-STING) signalling pathway is an element of the innate immune response and is activated by the presence of DNA in the cytosol. Triggering of this immune response may occur in the setting of infection or neoplasia. Activation of this pathway results in phosphorylation of interferon regulatory factor 3 and downstream transcription of cytokines such as interferon β and interleukin-6. Polyinosinic:polycytidylic acid (Poly (I:C)) is a synthetic double-stranded RNA analogue which activates the innate immune system. Previous research suggests that the phenotype of AIP-mutated pituitary tumours is shaped by their tumour microenvironment.
Aim: The aim of this work was to assess the expression of genes involved in cGAS-STING signalling in an Aip knockout cell line.
Methods: RT-qPCR was used to assess gene expression in wild-type and Aip knockout mouse embryonic fibroblasts following six hours of treatment with Poly(I:C) or vehicle.
Results: Aip knockout was first successfully confirmed by qPCR and western blotting. Knockout cells treated with vehicle showed significantly increased expression levels of Irf3 (P=0.0002), Ifnb (P=0.004) and Il6 (P=0.003) compared to wild-type vehicle treated cells. In addition, following treatment with Poly(I:C), there appeared to be further significant enhanced expression of the cGAS-STING pathway downstream gene Irf3 (P=0.02) in Aip knockout cells versus wild-type cells. Ifnb downstream of Irf3 and Il6 downstream of Nfkb1 showed a trend for enhanced expression in Aip knockout versus wild-type cells treated with Poly(I:C), but this did not reach significance.
Conclusions: The data suggest that lack of Aip results in increased inflammatory cytokine gene expression with increased responsiveness to the Poly(I:C) STING agonist. This would correspond with our previous data with more inflammatory infiltration in AIP mutant human and mouse tumours.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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