Critical Role of the HMGA2 Gene in Pituitary Adenomas

Abstract

The molecular pathway leading to pituitary tumorigenesis is still largely unknown and is one of the challenges of the endocrine oncology. The development of pituitary adenomas in HMGA2 transgenic mice and the finding of HMGA2 amplification and overexpression in human pituitary adenomas led us to investigate the mechanism by which the HMGA2 gene plays a crucial role in pituitary oncogenesis. This mechanism has been recently described by our group: it entails the acetylation of E2F1, and its consequent enhanced activity, following the displacement of HDAC1 from the pRB/E2F1 inhibitory complex. Based on the mating between HMGA2 transgenic and E2F1 knockout mice, the activation of E2F1 appears to be the main mechanism of the onset of HMGA2-induced pituitary adenoma development. Nevertheless, other events may be also involved in this process, and are discussed here.

Epidrug mediated re-expression of miRNA targeting the HMGA transcripts in pituitary cells

“…[8] Similarly, early reports describing inappropriate expression of the high mobility group A gene (HMGA2) showed this to be associated with genetic change, apparent as chromosomal amplification or re-arrangement. [9,10] However, more recent investigations now describe association between microRNA (miRNA) and the inappropriate expression of HMGA2 and also that of the HMGA1 gene. [11] In these cases, increase in HMGA1 and HMGA2 expression is associated with loss or significantly reduced expression of miRNA that target these gene transcripts.…”

Prolactinoma in Children and Adolescents

“…The HMGA2 proteins are low-molecular-weight nuclear factors that interact with the minor groove of many AT-rich promoters and enhancers [12]. It has been recognized that HMGA2 is substantially expressed in tumor cells from human prolactinomas [11]. Interestingly, microarray analyses identified 726 unique genes that were statistically significantly different between prolactinomas and normal glands, whereas proteomic analysis identified 4 differently upregulated and 19 downregulated proteins [13].…”

“…Additionally, the role of the high mobility group A 2 (HMGA2) gene in the genesis of pituitary adenomas in humans has been recently demonstrated [11]. The HMGA2 proteins are low-molecular-weight nuclear factors that interact with the minor groove of many AT-rich promoters and enhancers [12].…”

The Mia/Cd-rap gene expression is downregulated by the high-mobility group A proteins in mouse pituitary adenomas

“…In fact, these mice allowed us to demonstrate that the mechanism of the HMGA2-induced pituitary adenoma development is based on the increased E2F1 activity (Fedele et al 2006b). Since other additional mechanisms can be envisaged on the base of a minimal residual tumoral phenotype showed by some HMGA2 transgenic mice lacking a functional E2F1 gene (Fedele et al 2006c), in the present study we have analyzed the gene expression profile of three HMGA2-pituitary adenomas in comparison with a pool of ten normal pituitary glands in order to identify other genes involved in the process of pituitary tumorigenesis induced by the HMGA2 gene. The results of our analysis led to the identification of 82 transcripts that increased and 72 transcripts that decreased at least fourfold in all mice pituitary adenomas analyzed when compared with normal pituitary gland.…”