ECE2023 Poster Presentations Adrenal and Cardiovascular Endocrinology (72 abstracts)
Insulin-like growth factor 2 (IGF2) system role in promoting cell growth in different adrenocortical carcinoma (ACC) cell models
Rosa Catalano 1 , Emma Nozza 1,2 , Emanuela Esposito 1,2 , Anna Maria Barbieri 1 , Giusy Marra 1 , Donatella Treppiedi 3 , Genesio Di Muro 1,4 , Federica Mangili 3 , Hantel Constanze 5,6 , Sandra Sigala 7 , Elisa Cassinotti 8 , Ludovica Baldari 8 , Valentina Morelli 9 , Serena Palmieri 3 , Sofia Frigerio 3 , Emanuele Ferrante 3 , Maura Arosio 1,3 , Giovanna Mantovani 1,3 & Erika Peverelli 1,3
1University of Milan, Department of Clinical Sciences and Community Health, Milan, Italy; 2University of Milan, PhD Program in Experimental Medicine, Milan, Italy; 3Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Endocrinology unit, Milan, Italy; 4University Sapienza of Rome, PhD Program in Endocrinological Sciences, Rome, Italy; 5University Hospital Zurich (USZ) and University of Zurich (UZH), Department of Endocrinology, Diabetology and Clinical Nutrition, Zurich, Switzerland; 6University Hospital Carl Gustav Carus Dresden, Medizinische Klinik und Poliklinik III, Dresden, Germany; 7University of Brescia, Department of Molecular and Translational Medicine, Section of Pharmacology, Brescia, Italy; 8Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Department of Surgery, Milan, Italy; 9Istituto Auxologico Italiano, IRCCS, Unit for Bone Metabolism Diseases and Diabetes, Milan, Italy
The majority of adrenocortical carcinomas (ACC) overexpress insulin-like growth factor 2 (IGF2). Although IGF2 drives a proliferative autocrine loop by binding to IGF1R and the isoform A of the insulin receptor (IRA), most studies focused on IGF1R. Recently, a high expression of IRA was observed in ACC vs normal adrenal tissues (NA), suggesting its potential involvement in modulating IGF2 effects in adrenocortical tumorigenesis. Aim of this study was to investigate the specific roles of IGF1R and IR in mediating IGF2 tumorigenic effects in ACC. Western blot analyses showed a higher IGF1R protein expression in both ACC (n=8) and adrenocortical adenomas (ACA, n=8) vs NA (n=8) (mean 1.04±0.88 and 1.29±1.11 vs 0.36±0.12, respectively). Interestingly, although real-time qPCR showed a high variability and no significant differences in IGF1R, IR, IRA and IRB expression among the 3 groups, IRA/IRB ratio was higher than 2 in 5/8 (62.5%) ACC, 1/8 (12.5%) ACA and 0/8 (0%) NA, further supporting an implication of IRA in IGF2 pathway in ACC. Genetic silencing of IGF1R, IR and IGF1R+IR was performed in human ACC cell lines derived from both primary tumor (H295R) and metastasis (MUC-1, TVBF-7) and in 2 primary ACC cultures derived from primary tumor. All cell models used presented an active IGF2 autocrine loop, as demonstrated by the ELISA assay measuring the presence of IGF2 in culture media. We observed different effects of IGF1R and/or IR knockdown on cell proliferation depending on the cell model. In H295R, neither single nor double IGF1R and IR silencing had an effect on cell proliferation, with no variation on cyclin E1 and B1 expression. Likewise, no changes were detected in ACC primary cultured cells after IGF1R or IR silencing. Instead, in MUC-1 IGF1R knockdown decreased cell proliferation (-19.32±15.48%, P<0.01) and cyclin E1 expression (-30±25%, P<0.05), and a further reduction was observed in IGF1R+IR silenced cells (-47.21±7.18%, P<0.001 vs bas and P<0.01 vs cells silenced for IGF1R) with a diminished expression of both cyclin E1 (-36±26%, P<0.05) and cyclin B1 (-55±37%, P<0.01). Similarly, in TVBF-7, even if no variations were found after IGF1R or IR silencing, a significant reduction was observed in IGF1R+IR silenced cells (-44.08±10.52%, P<0.001). In conclusion, our preliminary data showed a high heterogeneity among different cell models with a tumor-specific role of IGF1R and IR, and seem to suggest that these receptors play a key role in promoting cell growth in ACC metastases but not in primary tumor.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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