Reciprocal Changes in the Expression of Transcription Factors GATA-4 and GATA-6 Accompany Adrenocortical Tumorigenesis in Mice and Humans

Abstract

While certain genetic changes are frequently found in adrenocortical carcinoma cells, the molecular basis of adrenocortical tumorigenesis remains poorly understood. Given that the transcription factors GATA-4 and GATA-6 have been implicated in gene expression and cellular differentiation in a variety of tissues, including endocrine organs such as testis, we have now examined their expression in the developing adrenal gland, as well as in adrenocortical cell lines and tumors from mice and humans. Northern blot analysis and in situ hybridization revealed abundant GATA-6 mRNA in the fetal and postnatal adrenal cortex of the mouse. In contrast, little or no GATA-4 expression was detected in adrenal tissue during normal development. In vivo stimulation with ACTH or suppression with dexamethasone did not affect the expression of GATA-4 or GATA-6 in the murine adrenal gland. To assess whether changes in the expression of GATA-4 or GATA-6 accompany adrenocortical tumori-genesis, we employed an established mouse model. When gonadectomized, inhibin a/SV40 T-antigen transgenic mice develop adrenocortical tumors in a gonadotropin-dependent fashion. In striking contrast to the normal adrenal glands, GATA-6 mRNA was absent from adrenocortical tumors or tumor-derived cell lines, while GATA-4 mRNA and protein were abundantly expressed in the tumors and tumor cell lines. Analogous results were obtained with human tissue samples; GATA-4 expression was detected in human adrenocortical carcinomas but not in normal tissue, adenomas, or pheochromocytomas. Taken together these results suggest different roles for GATA-4 and GATA-6 in the adrenal gland, and implicate GATA-4 in adrenal tumorigenesis. Immunohistochemical detection of GATA-4 may serve as a useful marker in the differential diagnosis of human adrenal tumors.

Distinct Expression ofCDX2 andGATA4/5, Development-Related Genes, in Human Gastric Cancer Cell Lines

“…(iii) GATA4/5/6 transcription factors have distinct functions in the regulation of intestinal epithelial cell differentiation [13]. (iv) Evidence has been obtained showing a link between GATA binding proteins and adrenocortical tumors in mice and humans [24]. In our study, GATA4 and GATA5 were downregulated in some of the gastric cancer cell lines, implying the possible involvement of these two genes in the carcinogenesis of the stomach.…”

Increased Steroidogenic Factor-1 Dosage Triggers Adrenocortical Cell Proliferation and Cancer

“…Those tumors are thought to be derived from pluripotent adrenogonadal precursor cells lying beneath the outer adrenal connective capsule, which in the susceptible strains still have the potential to differentiate into cells of gonadal stroma phenotype (14)(15)(16). In rare cases, human ACT can express LH receptors, in cases of both cortisol-and aldosterone-producing neoplasms, and GATA-4 (63)(64)(65)(66). These data, together with the relatively common finding of adrenal rests in the testes of male patients with congenital adrenal hyperplasia (67), suggest that also in humans, pluripotent precursor cells can be found in both adrenals and gonads.…”

Steroid Sulfotransferase 2A1 Gene Transcription Is Regulated by Steroidogenic Factor 1 and GATA-6 in the Human Adrenal

“…We and others have recently demonstrated the presence of GATA-6 and GATA-4 in the human adrenal cortex and ovarian follicle, respectively (22,(35)(36)(37). Using real-time RT-PCR the expression of GATA-6 and GATA-4 transcripts was further characterized in adrenal as well as liver for comparison.…”