To address the question whether HMGA2 is only upregulated in the 12q14-15 subgroup, the expression of HMGA2 was analyzed in a comprehensive set of leiomyomas (n = 180) including tumors with 12q14-15 chromosomal aberrations (n = 13) and matching myometrial tissues (n = 51) by quantitative RT-PCR.
From the results of the present study, it is evident that expression of HMGICcannot simply be considered a sign of neoplasia or an effect of proliferation.
In contrast, HMGI-C expression is down-regulated during the development of the adrenal gland, completely absent in the adult individual, and only detectable in a subset of ex vivo NB tumors and in RA-resistant NB cell lines.
In a totally benign endometrial polyp, double minute chromosomes were shown to contain an amplified and apparently nonrearranged HMGIC gene, expressed in the tumor cells, suggesting amplification of HMGIC through double minute chromosome formation as another hitherto unreported mechanism associated with the development of some mesenchymal tumors.
HMGA2 overexpression in ULM is not only related to tumor development but also plays a role in controlling cellular proliferation through the AKT pathway.
The presence of activated pCHK1(Ser296) coincided with prolonged G2/M block and increased tumor cell survival, which was enhanced further in the presence of HMGA2.
A significant difference was found in the HMGA2 expression levels between the different grading groups (one-way ANOVA, P = 0.04) and among the fusion-negative and -positive tumors (t-test, P = 0.05), indicating that the expression level of HMGA2 was closely linked to grading, the presence/absence of the CRTC1-MAML2 fusion, and the tumor behavior of MECs.
RT-PCR-based expression studies of 4 of these HMGA2 transcripts revealed a co-expression with the "wild-type" HMGA2a in tumor samples as well as in normal tissues.
In this study the activation of HMGA2 and overexpression by FGF1-driven stimulation of adipose tissue derived stem cells (ADSCs) in adipose tissue tumors were analyzed.
Chromosomal translocations of HMGA2 are common in mesenchymal tumors, whereas the regulatory mechanisms of HMGA2 in malignant epithelial tumors are much more complex.
Seventy adipocytic tumors, representing different morphologic and cytogenetic subgroups, were analyzed by qRT-PCR to study the expression status of HMGA2; 18 of these tumors were further examined by PCR to search for mutations or deletions in the 3'UTR.
Previously, HMGA2 was shown to be misexpressed in a number of benign, differentiated mesenchymal tumors including lipomas, uterine leiomyomas, and pulmonary chondroid hamartomas.
Fluorescence in situ hybridization with a BAC clone covering the 5' region produced three signals versus two signals with a BAC clone covering the 3' region including intron 3 of HMGA2, which harbors most of the breakpoints described in benign mesenchymal tumors.
The observed pattern is similar to rearrangements of HMGA2 found in several other benign mesenchymal tumors, i.e., disruption of the HMGA2 locus leaves intact exons 1-3 which encode the AT-hook domains and separates them from the 3'-terminal part of the gene.
Furthermore, high-mobility group AT-hook 2 expression in the fibro-adipocytes of this tumor indicated that these cells are an integral component of the pancreatic lipomatous hamartoma.
Thus, intragenic rearrangements within the LHFP gene leading to its fusion to HMGIC are not a consistent finding in mesenchymal tumors with clonal aberrations of both chromosomal regions 12q13 through q15 and 13q12 through q14.
By FISH with cosmids spanning the gene encoding the high-mobility-group protein HMGIC, we were able to show a rearrangement within or close to HMGIC in all tumors with 12q14-15 abnormalities tested, in 11 tumors with an apparently normal karyotype, and in 4 tumors with complex abnormalities without cytogenetically visible alterations of chromosomes 12.
Recent data suggest that mutations of the mediator subcomplex 12 gene (MED12) and rearrangements of the gene-encoding high-mobility group protein AT-hook 2 (HMGA2) characterize major genetic subtypes of these tumors, which, for example, differ by their average size.
Four of seven ectopic sequences previously described to be fused to exon 4 of HMGIC in different tumors were found to be located within intron 4 of the gene and thus are due to abnormal splicing.
Genome-wide studies reveal upregulation of the HMGI-C gene in many human cancers, which suggests that HMGI-C might play a critical role in the progression of various tumors.