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Endocrine Abstracts (2016) 41 OC9.2 | DOI: 10.1530/endoabs.41.OC9.2

ECE2016 Oral Communications Endocrine Tumours (5 abstracts)

Role of luteinizing hormone receptor in the ontogeny and progression of adrenocortical tumors in transgenic mice expressing SV40Tag under the inhibin-α promoter

Milena Doroszko 1 , Marcin Chrusciel 1, , Kirstine Belling 3 , Susanna Vuorenoja 1 , Marlene Dalgaard 3 , Henrik Leffers 3 , H Bjørn Nielsen 3 , Ilpo Huhtaniemi 1, , Jorma Toppari 1, & Nafis Rahman 1,


1Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland; 2Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, Bialystok, Poland; 3Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark; 4Institute of Reproductive and Developmental Biology, Imperial College London, London, UK; 5Department of Pediatrics, University of Turku, Turku, Finland.


: We analyzed the occurrence of adrenocortical tumors in transgenic mice expressing Simian Virus 40 T antigen (SV40Tag) under the inhibin-α promoter (inhα/Tag) and searched for novel biomarker genes for the tumorigenesis. We studied 2-, 4-, 6-mo-old intact (never forming tumors) and prepubertally gonadectomized (GDX) inhα/Tag mice (developing tumors) and similar groups of wild-type mice as controls. Furthermore, the role of ectopic luteinizing hormone receptor (Lhcgr) expression in the tumors was explored by crossbreeding inhα/Tag mice with Lhcgr deficient mice (inhα/Tag/LuRKO) and by treating tumor-bearing GDX inhα/Tag mice with human chorionic gonadotropin (5 IU/week/for 3 weeks). In both sexes, the expression of Grb10, Mmp24, Sgcd, Rerg, Gnas, Nfatc1, Gnrhr, Igf2 was significantly downregulated; whereas that of Esr1, PrlRL, Gata-4 and Lhcgr was upregulated in the tumorous vs. GDX wild-type adrenal gland. Sex steroid enzyme genes (Srd5a1, Cyp19a1) were also upregulated, but adrenal-specific steroidogenic enzymes (Cyp21a1, Cyp11b1, Cyp11b2) downregulated. Inhibin-α expression was scattered throughout the adrenal cortex of GDX inhα/Tag mice. SV40Tag expression was restricted to the upper layers of zona fasciculata in GDX inhα/Tag mice, but in intact mice to the subcapsular region, infiltrating cortex towards medulla along with aging/tumor progression. Adrenal tumors failed to form in GDX inhα/Tag/LuRKO double transgenic mice. In vivo hCG treatment increased plasma progesterone concentrations in GDX inhα/Tag, but did not affect the tumor progression.

Taken together, our results suggest that adrenal LH/LHCGR function was a prerequisite for tumor formation after GDX in Inhα/Tag, but not required for tumor progression. Downregulated genes found in the tumor tissues suggest their necessity in the normal adrenocortical phenotype development. Upregulated genes may serve as potential biomarker candidates for adrenocortical tumorigenesis. The steroidogenic enzyme gene expression pattern in inhα/Tag mice may suggest increased sex steroid hormone production (androgens, estrogens) at the expense of adrenal hormone steroidogenesis (corticosterone, aldosterone).

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