Transgenic GATA-4 expression induced adrenocortical tumorigenesis is dependent on genetic susceptibility

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SUN 17-28-Adrenal Tumors & Pheochromocytoma
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-21
Nafis Ahmed Rahman*1, Marcin Chrusciel1, Milena Doroszko1, Adolfo Rivero Muller1, Xiangdong Li2, Jorma Toppari3 and Ilpo T. Huhtaniemi4
1University of Turku, Turku, Finland, 2China Agricultural University, Beijing, China, 3Univ of Turku, Turku, Finland, 4Imperial College London, London, United Kingdom
The highly upregulated expression of GATA-4 transcription factor in neoplastic cells of murine and human adrenocortical tumors showed its potential as a biormarker candidate. In order to assess the role of GATA-4 in the pathomechanisms of adrenocortical tumorigenesis, we transgenically expressed Gata4 under the 21-hydroxylase promoter (Cyp21a1, 21-OH) in C57Bl/6N (21-OH-GATA-4) and DBA (21-OH-G4-DBA) mice. The latter has been found to be genetically susceptible to gonadotropin-dependent adrenocortical neoplasia, whereas C57BL/6 mice are non-susceptible. There was a gradual age-dependent increase of GATA-4 expression in both female and male adrenals of the 21-OH-G4-DBAmice, whereas in 21-OH-GATA-4, only in female mice adrenals. Evident adrenocortical neoplasia of non-steroidogenic spindle-shaped “A” cells in the subcapsular cortex was observed in adrenals of 21-OH-G4-DBA females and males at age of 2-mo and 4-mo, respectively, while in 21-OH-GATA-4 adrenals they were found at 6-mo-old females. Both TG murine lines displayed elevated expression of FOG-2 that was co-localized with GATA-4 in “A” cells. GATA-6 expression was non-detectable in “A” cells of both 21-OH-GATA-4 and 21-OH-G4-DBA TG murine adrenals. Additionally, Gata6 expression measured from the total mRNA was significantly downregulated but only in 21-OH-GATA-4 adrenals compared to control WT littermates. Gonadectomy (GDX) on 21-OH-GATA-4, apparently through direct action of elevated serum LH, markedly enhanced the adrenocortical neoplasia, which now also appeared in TG males. The neoplastic areas of the post-GDX 21-OH-GATA-4 adrenals contained, besides “A” cells, larger lipid-laden, steroidogenically active and LHCGR positive “B” cells. Prolonged (>10 months, mo) exposure to elevated post-GDX LH levels resulted in formation of adrenocortical adenomas in the 21-OH-GATA-4 mice. Our findings showed that transgenic GATA-4 expression induces GDX-independent adrenocortical neoplasia and its ontogeny and progression depends on the mouse-strain being genetic susceptibility towards adrenocortical tumorigenesis.

Nothing to Disclose: NAR, MC, MD, AR, XL, JT, ITH

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