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

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.

• Authors: Milena Doroszko, Marcin Chrusciel, Joanna Stelmaszewska, Tomasz Slezak, Adolfo Rivero-Muller, Artur Padzik, Slawomir Anisimowicz, Slawomir Wolczynski, Ilpo Huhtaniemi, Jorma Toppari, Nafis A Rahman
• Journal: Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology (Cell Physiol Biochem) Vol. 43 Issue 3 Pg. 1064-1076 ( 2017) ISSN: 1421-9778 [Electronic] Germany
• PMID: 28977799 (Publication Type: Journal Article)
• Copyright: © 2017 The Author(s). Published by S. Karger AG, Basel.

Chemical References

• Antigens, Polyomavirus Transforming
• GATA4 Transcription Factor
• GATA6 Transcription Factor
• Phosphoproteins
• Receptors, LH
• Steroidogenic Factor 1
• inhibin-alpha subunit
• steroidogenic acute regulatory protein
• Inhibins
• Luteinizing Hormone
• Cholesterol Side-Chain Cleavage Enzyme
• Caspase 3

Topics

• Adrenal Cortex Neoplasms (etiology, metabolism, pathology)
• Adrenal Glands (metabolism, pathology)
• Animals
• Antigens, Polyomavirus Transforming (genetics, metabolism)
• Apoptosis
• CRISPR-Cas Systems (genetics)
• Caspase 3 (metabolism)
• Cell Proliferation
• Cell Transformation, Neoplastic
• Cholesterol Side-Chain Cleavage Enzyme (metabolism)
• Down-Regulation
• Female
• Fluoroimmunoassay
• GATA4 Transcription Factor (deficiency, genetics, metabolism)
• GATA6 Transcription Factor (metabolism)
• Gonads (surgery)
• Inhibins (genetics, metabolism)
• Luteinizing Hormone (blood, metabolism)
• Mice
• Mice, Knockout
• Mice, Transgenic
• Phenotype
• Phosphoproteins (metabolism)
• Receptors, LH (deficiency, genetics)
• Steroidogenic Factor 1 (metabolism)