Gene expression profile analysis of pituitary adenomas developed by HMGA transgenic mice

Abstract

The High Mobility Group A (HMGA) nonhistone chromatin proteins alter chromatin structure and, thereby, regulate the transcription of several genes by either enhancing or suppressing transcription factors. This protein family is implicated, through different mechanisms, in both benign and malignant neoplasias. Rearrangements of HMGA genes are a feature of most benign human mesenchymal tumors. Conversely, unrearranged HMGA overexpression is a feature of malignant tumors and is also causally related to neoplastic cell transformation. Recently, we have generated transgenic mice carrying wild type or truncated HMGA genes under transcriptional control of the cytomegalovirus promoter. These mice developed pituitary adenomas secreting prolactin and growth hormone. We have recently demonstrated that the mechanism of the HMGA2 induced-pituitary tumorigenesis is based on the increased E2F1 activity. To identify other genes involved in the process of pituitary tumorigenesis induced by the HMGA2 and HMGA1 genes, we have analysed here the gene expression profile of HMGA2- and HMGA1-induced pituitary adenomas in comparison with a pool of ten normal pituitary glands from control mice using the Affymetrix MG MU11K oligonucleotide array representing ~ 13,000 unique genes. We have identified 82 transcripts increased and 72 transcripts decreased of at least 4-fold in all mice pituitary adenomas analyzed compared to normal pituitary gland. The microarray results have been confirmed by semi-quantitative RT-PCR on RNA extracted from different HMGA2- and HMGA1-induced mouse pituitary adenomas. Then, we focused our attention on the Mia/Cd-rap and Cyclin B2 gene, the first down-regulated and the second up-regulated in all pituitary adenomas tested by the microarray. We demonstrated that the HMGA proteins directly bind and regulate their promoters.