ECE2023 Rapid Communications Rapid Communications 5: Adrenal and Cardiovascular Endocrinology 1 (6 abstracts)
IGF2R: a new player in the insulin-like growth factor 2 (IGF2) pathway sustaining adrenocortical carcinoma cells growth
Emma Nozza 1,2 , Rosa Catalano 1 , 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 , 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, Milano, 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, Section of Pharmacology, Department of Molecular and Translational Medicine, Brescia, Italy
Adrenocortical carcinomas (ACC) are rare endocrine tumors that originate in the cortex of the adrenal gland. They are characterized by the overexpression of insulin-like growth factor 2 (IGF2), whose bond with two tyrosine-kinase receptors, IGF1R and IR, activates a cancer-promoting signalling cascade. Another component of the IGF system is mannose 6-phosphate/insulin-like growth factor 2 receptor (IGF2R), a scavenger receptor able to bind specifically IGF2. Its main role is to internalise IGF2 and direct it to lysosomal degradation, suggesting an anti-oncogenic role. However, the study of its involvement in different tumors has highlighted a diverse role, even making it a marker of poor prognosis. Aim of the present study was to deepen the knowledge on IGF2R role in ACC investigating its expression levels, involvement in the proliferative mechanism and interaction with the other receptors of the IGF2 pathway. IGF2R expression was evaluated in two human ACC cell lines (MUC-1 and H295R), 7 ACC tissue samples, and 7 normal adrenal tissues (NA). Our results showed that ACC tissues and cell lines had increased IGF2R protein levels compared to NA (P<0.01). To investigate IGF2R role in cell proliferation we altered its expression in MUC-1 and H295R cell lines. We demonstrated that IGF2R genetic silencing reduced cell proliferation (-11.65±8.73% P<0.01 in MUC-1; -14.02±12.35% P<0.01 in H295R). Similarly, IGF2R-neutralizing antibody incubation exerted anti-mitotic effects (-16.85±2.57% P<0.05 in MUC-1). On the opposite, IGF2R transient transfection promoted cell growth (+14.84±12.54% P<0.01 in MUC-1; +24.49±15.62% P<0.001 in H295R). To investigate the molecular mechanism involved, we tested the effect of IGF2R manipulations on the expression of the other receptors of the IGF2 pathway. MUC-1 silenced for IGF2R showed a significant decrease in IGF1R protein expression (-35 ±37% P<0.05); accordingly, after IGF2R transfection, IGF1R protein level was increased (+20±6% P<0.001). In conclusion, IGF2R is involved in the mechanisms driving cell proliferation in ACC, possibly relating also to the alteration of IGF1R expression. Since its upregulation in ACC and its pro-mitotic action, IGF2R may represent a promising therapeutic target for the treatment of ACC.
Volume 90
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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