Transgenic mice overexpressing the wild-type form of the HMGA1 gene develop mixed growth hormone/prolactin cell pituitary adenomas and natural killer cell lymphomas

Abstract

Overexpression of HMGA1 proteins is a constant feature of human carcinomas. Moreover, rearrangements of this gene have been detected in several human benign tumors of mesenchymal origin. To define the role of these proteins in cell transformation in vivo, we have generated transgenic mice overexpressing ubiquitously the HMGA1 gene. These mice developed mixed growth hormone/prolactin cell pituitary adenomas and natural killer (NK)-T/NK cell lymphomas. The HMGA1-induced expression of IL-2 and IL-15 proteins and their receptors may account for the onset of these lymphomas. At odds with mice overexpressing a wild-type or a truncated HMGA2 protein, adrenal medullar hyperplasia and pancreatic islet cell hyperplasia frequently occurred and no increase in body size and weight was observed in HMGA1 mice. Taken together, these data indicate an oncogenic role of the HMGA1 gene also in vivo.

Regulation of microRNA expression by HMGA1 proteins

“…Several studies indicate that HMGA gene overexpression plays a critical role in the process of carcinogenesis and their oncogenic activity has been demonstrated in vitro and in vivo (Fusco and Fedele, 2007). In fact, either HMGA1 or HMGA2 overexpression is able to transform mouse and rat fibroblasts (Fedele et al, 1998;Scala et al, 2000), and transgenic mice overexpressing either HMGA1 or HMGA2 develop natural killer-T lymphomas and pituitary adenomas (Baldassarre et al, 2001;Fedele et al, 2002Fedele et al, , 2005. Interestingly, the HMGA1 gene also seems to have a tumor suppressor role in oncogenesis since the Hmga1-null mice, even at the heterozygous state, develop B-cell lymphomas and myeloid malignancies, other than cardiac hypertrophy and type II diabetes (Foti et al, 2005;Fedele et al, 2006).…”

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

“…Convincing evidence for the role of these genes, and their protein products, in tumour evolution are provided through studies in transgenic mice, where, enforced expression of either hmga1 or hmga2 leads to the development of pituitary adenomas. [36][37][38] Although inappropriate expression of HMGA2 in a proportion of prolactinoma is associated with chromosome rearrangement or amplification [39] in other pituitary adenoma subtypes, overexpression of HMGA2 and also that of HMGA1, are not associated with these types of genetic perturbations. However, in these cases, loss or significantly reduced expression of target-specific miRNA, which contemporaneously target each of these transcripts, has been described.…”

Downregulation of miR-410 targeting the cyclin B1 gene plays a role in pituitary gonadotroph tumors

“…Indeed, we previously demonstrated that another member of cyclin B family, CCNB2, was increased in pituitary adenomas with respect to normal pituitary 14 and that its expression was mainly regulated by the HMGA1 and HMGA2 proteins whose overexpression represents an important event in pituitary adenomas as also demonstrated by the development of GH/ PRL adenomas in transgenic mice overexpressing these genes. 15 Moreover, cyclin B1 regulates the G2/M transition in the cell cycle, and its appropriate regulation is essential for mitosis initiation. 28 Therefore, a deregulated expression of CCNB1 could play a critical role in pituitary tumor development, since the regulation of the cell cycle is a complex network that includes many regulatory molecules, and the deregulation of the cell cycle and its effectors is the key mechanism in pituitary tumors.…”

“…In fact, HMGA proteins are overexpressed in most of the human pituitary adenomas. 13,14 Moreover transgenic mice overexpressing these genes developed mixed PRL/GH pituitary adenomas 15 and increased E2F1 activity or expression can lead to pituitary tumorigenesis. 16,17 Furthermore, Leone et.…”