GATA-4 overexpression induces adrenocortical tumorigenesis and ectopic expression of luteinizing hormone receptor in C57Bl/6J mice
M. Chrusciel1,2, S. Vuorenoja1, B. Mohanty1, A. Rivero-Müller1, Z. Lei3, J. Toppari1, X. Li4, I. Huhtaniemi1,5 & N. Rahman1,6
We have earlier shown a reciprocal feed-forward amplification link between expression of transcription factor GATA-4 and luteinizing hormone receptor (LHR) during adrenocortical tumorigenesis, and also that chronically elevated LH levels may induce LHR in mice, but not GATA-4. Hereby, our goal was to analyze the consequences of ectopically expressed GATA-4 on murine adrenal cortex in the presence and absence of gonadectomy (GDX) induced elevated LH levels. For this purpose, we established a transgenic (TG) murine model overexpressing ectopically GATA-4 under the adrenal specific 21-hydroxylase (21-OH) promoter (21-OH-GATA-4) in C57Bl/6J genetic background. In intact 21-OH-GATA-4 females, but not in males, a gradual age-dependent increase of adrenal Gata-4 expression was followed by slowly progressing hyperplasia of non-steroidogenic spindle-shaped cells (A cells) in the subcapsular cortex. This phenotype was markedly enhanced by GDX in both sexes. Additionally, adrenocortical hyperplastic areas of GDX 21-OH-GATA-4 mice, besides A cells, were also composed with large lipid-laden cells (B cells). Long exposure on elevated LH levels resulted with adrenocortical adenoma in 21-OH-GATA-4 females. Intact and GDX 21-OH-GATA-4 adrenals displayed high Fog-2 but downregulated Gata-6 expression. In contrast to WT adrenal cortex and neoplastic B cells, areas with spindle-shaped A cells in intact and GDX 21-OH-GATA-4 mice were SF-1, DAX-1 and CYP11A1a negative. Both normal and neoplastic adrenocortical cells were StAR positive. 21-OH-GATA-4 mice of both sexes expressed ectopic LHR already by the age of 2 mo. LHR was localized in morphologically normal adrenocortical cells and large lipid-laden B cells of intact and GDX 21-OH-GATA-4 adrenals. Our findings provide the molecular pathways into the induction of adrenocortical tumorigenesis and expression of LHR as a consequence of ectopic adrenocortical expression of GATA-4.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This work was supported, however funding details are unavailable.