ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2019) 16 8.13 | DOI: 10.1530/ey.16.8.13

Institute of Biomedicine, University of Turku, Turku, Finland


To read the full abstract: Endocr Relat Cancer. 2019; 26(1): 103–117.

Incidence of adrenocortical carcinomas shows a bimodal distribution, being more common in children <10 years and in adults aged 40–50 years. Their prognosis is poor, with only 10–25% 5-year survival. Ectopic expression of LHCGR and GNRHR has been reported in ACTH-independent adrenal hyperplasia and in aldosterone-producing adrenal carcinomas, suggesting the possibility of GnRH analogues as a potential new treatment strategy.

This study investigated the expression of several GPCRs in human adrenocortical carcinomas (h-ACC) and mouse adrenal tumors, and further analyzed the molecular mechanisms of GnRH antagonist action on adrenocortical tumor (ACT) cells in vitro and in vivo. Thirteen formalin fixed h-ACC samples were assessed with: A) immunohistochemistry; B) in situ hybridization and qPCR to identify the expression of GPCRs.

The authors found that ACC expressed the genes GNRHR, LHCGR but not FSHR. Cell cultures of Cα1, Y-1 and H295 cell lines were treated with Cetrorelix acetate (CTX; a GnRH antagonist) and in all cells the cell viability and proliferation were decreased. Furthermore, GNRHR knock-down experiments in H295 cells confirmed that these CTX actions were mediated through GNRHR. They then used inhα/Tag mice to study the effects of CTX treatment on ACT in vivo. cDNA microarray analyses were run to identify the plausible biological processes and pathways affected by CTX in ACTs. Expressed genes were clustered with the PANTHER classification system and the most interesting processes were growth, biological adhesion, immune system, development and response to stimulus. Among dysregulated pathways, the authors identified p53, apoptosis signaling, EGFR signaling, FGF signaling, G-protein signaling pathways, angiogenesis and Wnt signaling pathways. CTX treatment of inhα/Tag mice showed that in the ACTs the expression of tumour biomarkers such as Gata4, Lhcgr, Cyclin A1 (Ccna1) was down-regulated, whereas expression of Sgcd and Mmp24 was up-regulated together with other genes related to cell growth suppression and tumour suppression. Taken together, the in vivo and in vitro data showed that GnRH antagonist treatment acts directly on ACC tumors to cause their regression.

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