Novel genes involved in pathophysiology of gonadotropin-dependent adrenal tumors in mice

Abstract

Specific inbred strains and transgenic inhibin-α Simian Virus 40 T antigen (inhα/Tag) mice are genetically susceptible to gonadectomy-induced adrenocortical neoplasias. We identified altered gene expression in prepubertally gonadectomized (GDX) inhα/Tag and wild-type (WT) mice. Besides earlier reported Gata4 and Lhcgr, we found up-regulated Esr1, Prlr-rs1, and down-regulated Grb10, Mmp24, Sgcd, Rerg, Gnas, Nfatc2, Gnrhr, Igf2 in inhα/Tag adrenal tumors. Sex-steroidogenic enzyme genes expression (Srd5a1, Cyp19a1) was up-regulated in tumors, but adrenal-specific steroidogenic enzyme (Cyp21a1, Cyp11b1, Cyp11b2) down-regulated. We localized novel Lhcgr transcripts in adrenal cortex parenchyma and in non-steroidogenic A cells, in GDX WT and in intact WT mice. We identified up-regulated Esr1 as a potential novel biomarker of gonadectomy-induced adrenocortical tumors in inhα/Tag mice presenting with an inverted adrenal-to-gonadal steroidogenic gene expression profile. A putative normal adrenal remodeling or tumor suppressor role of the down-regulated genes (e.g. Grb10, Rerg, Gnas, and Nfatc2) in the tumors remains to be addressed.

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

“…In contrast, a significant decrease of A cell biomarker Gata4 in OVX LuRKO and OVX inhα/Tag/LuRKO when compared to OVX WT adrenals, indicated a decrease in their population when LH/LHCGR signaling was lacking. An increase in A cell population after GDX [37], and Lhcgr expression in a sub-population of A cells [21] suggest that LHCGR signaling may affect their proliferation.…”

“…This corresponds to the impaired expression of steroidogenic enzymes in inhα/Tag males bearing adrenocortical tumors [21]. In vitro studies revealed that both Lhcgr and Gata4 are important regulators of general steroidogenic genes resulting in decreased progesterone production in Lhcgr-ko and Gata4-ko cells.…”

“…An adrenocortical tumor cell line (Cα1) has also been established from an inhα/Tag female founder [8] and extensively characterized [8, 17, 19]. Similar to other GIACT models, inhα/Tag adrenocortical tumors and Cα1 cells express an array of gonadal factors including Lhcgr and transcription factor GATA4 ( Gata4 ) [3, 8, 17, 21]. However, the direct involvement of LHCGR and GATA4 in the adrenocortical tumor induction, progression and phenotype, as well as their inter-relationship in these processes, remains unknown.…”

GnRH antagonist treatment of malignant adrenocortical tumors

“…Inhα/Tag mice, expressing Simian Virus 40T antigen under the inhibin α promoter, and with an intact immune system, are an example of a mouse model developing tumors (Kananen et al 1995, Chrusciel et al 2014. Intact inhα/Tag mice develop gonadal tumors, but when prepubertally gonadectomized, adrenocortical tumors appear with a hyperplasia-adenoma-adenocarcinoma sequence and abundant LHCGR expression (Kananen et al 1995, Rilianawati et al 1998, Rahman et al 2001, Bodek et al 2005, Vuorenoja et al 2007, Chrusciel et al 2014, Doroszko et al 2017a. The formation of gonadal and adrenocortical tumors in these mice is gonadotropin dependent, as gonadotropin genetic and pharmacological ablation prevented tumor growth (Rilianawati et al 1999).…”

“…Furthermore, elevated LH levels through cross-breeding to LHβ subunit overexpressing mice (LHβCT mice) (Risma et al 1995) resulted in simultaneous occurrence of gonadal and adrenocortical tumors (Mikola et al 2003). Our recent findings on inhα/ Tag mice showed that, besides LHCGR, the adrenocortical tumors express Gnrhr (Doroszko et al 2017a), and SV40Tag expression alone is only able to cause adrenocortical hyperplasia but not adenomas (Doroszko et al 2017b). The transition from hyperplasia to adenoma required LH/ LHCGR signaling, but thereafter tumor progression became gonadotropin independent (Doroszko et al 2017b).…”