title: Transgenic GATA-4 expression induces adrenocortical tumorigenesis in C57Bl/6 mice.
abstract: A link between elevated luteinizing hormone (LH) levels, GATA-4 and LH receptor (LHCGR) expression and gonadotropin-dependent adrenocortical tumorigenesis in humans and mice has been shown. To assess the mechanistic tumorigenic interrelationships between these factors, we transgenically expressed Gata4 under the 21-hydroxylase promoter (Cyp21a1, 21-OH) in C57Bl/6N mice. There was a gradual age-dependent increase of GATA-4 expression only in 21-OH-GATA-4 (TG) female adrenals, in association with slowly progressing neoplasia of non-steroidogenic spindle-shaped A cells in the subcapsular cortex. Gonadectomy (GDX), apparently through direct action of elevated serum LH, markedly enhanced the adrenocortical neoplasia, which now also appeared in GDX TG males. The neoplastic areas of the post-GDX TG adrenals contained, besides A cells, larger lipid-laden, steroidogenically active and LHCGR-positive B cells. Prolonged (>10 months) exposure to elevated post-GDX LH levels resulted in formation of adrenocortical adenomas in the TG mice. Intact and GDX TG mouse adrenals displayed elevated FOG-2 and decreased GATA-6 expression. Additionally, increased expression/activation of components of the Inhbb-Acvr2a-Acvr1c-Smad2/3 signaling system was observed in 12-month-old GDX TG adrenals. Our findings show that two distinct GATA-4-dependent populations of neoplastic adrenocortical cells form: non-steroidogenic LH-independent A cells and steroidogenic LH-dependent B cells.
authors: Department of Physiology, Institute of Biomedicine, University of Turku, FIN-20520, Finland.
authors: Marcin
authors: M
authors: Chrusciel
authors: Susanna
authors: S
authors: Vuorenoja
authors: Bidut
authors: B
authors: Mohanty
authors: Adolfo
authors: A
authors: Rivero-Müller
authors: Xiangdong
authors: X
authors: Li
authors: Jorma
authors: J
authors: Toppari
authors: Ilpo
authors: I
authors: Huhtaniemi
authors: Nafis A
authors: NA
authors: Rahman
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation; D005260:Female; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015151:Immunoblotting; D007150:Immunohistochemistry; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011974:Receptors, LH; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D050991:GATA4 Transcription Factor; D011974:Receptors, LH; D007986:Luteinizing Hormone
keywords: Adrenal; GATA-4; Gonadectomy; LH; LHCGR; LHR; Luteinizing hormone; Tumor