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Cell Physiol Biochem. 2017;43(3):1064-1076. doi: 10.1159/000481718. Epub 2017 Oct 4.

Luteinizing Hormone and GATA4 Action in the Adrenocortical Tumorigenesis of Gonadectomized Female Mice.

Author information

1
Institute of Biomedicine, University of Turku, Turku, Finland.
2
Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, Bialystok, Poland.
3
Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois, USA.
4
Turku Center for Biotechnology, Åbo Akademi and University of Turku, Turku, Finland.
5
Department of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin, Poland.
6
Center of Gynecology and Reproductive Endocrinology Artemida, Bialystok, Poland.
7
Institute of Reproductive and Developmental Biology, Imperial College London, London, United Kingdom.
8
Department of Pediatrics, Turku University Hospital, Turku, Finland.

Abstract

BACKGROUND/AIMS:

Physiological role of luteinizing hormone (LH) and its receptor (LHCGR) in adrenal remains unknown. In inhibin-α/Simian Virus 40 T antigen (SV40Tag) (inhα/Tag) mice, gonadectomy-induced (OVX) elevated LH triggers the growth of transcription factor GATA4 (GATA4)-positive adrenocortical tumors in a hyperplasia-adenoma-adenocarcinoma sequence.

METHODS:

We investigated the role of LHCGR in tumor induction, by crossbreeding inhα/Tag with Lhcgr knockout (LuRKO) mice. By knocking out Lhcgr and Gata4 in Cα1 adrenocortical cells (Lhcgr-ko, Gata4-ko) we tested their role in tumor progression.

RESULTS:

Adrenal tumors of OVX inhα/Tag mice develop from the hyperplastic cells localized in the topmost layer of zona fasciculata. OVX inhα/Tag/LuRKO only developed SV40Tag positive hyperplastic cells that were GATA4 negative, cleaved caspase-3 positive and did not progress into adenoma. In contrast to Lhcgr-ko, Gata4-ko Cα1 cells presented decreased proliferation, increased apoptosis, decreased expression of Inha, SV40Tag and Lhcgr tumor markers, as well as up-regulated adrenal- and down-regulated sex steroid gene expression. Both Gata4-ko and Lhcgr-ko Cα1 cells had decreased expression of steroidogenic genes resulting in decreased basal progesterone production.

CONCLUSION:

Our data indicate that LH/LHCGR signaling is critical for the adrenal cell reprogramming by GATA4 induction prompting adenoma formation and gonadal-like phenotype of the adrenocortical tumors in inhα/Tag mice.

KEYWORDS:

Adrenocortical tumors; GATA4; Lhcgr; Molecular mechanisms; Transgenic mice

PMID:
28977799
DOI:
10.1159/000481718
[Indexed for MEDLINE]
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