Overexpression of <i>HMGA2</i> in uterine leiomyomas points to its general role for the pathogenesis of the disease

Klemke, Markus; Meyer, Anke; Nezhad, Maliheh Hashemi; Bartnitzke, Sabine; Drieschner, Norbert; Frantzen, Christiane; Schmidt, Ernst Heinrich; Belge, Gazanfer; Bullerdiek, Jörn

doi:10.1002/gcc.20627

Cited by 58 publications

(45 citation statements)

References 35 publications

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“…In the remaining case without elevated HMGA2 expression despite a cytogenetically visible t(12;14)(q15;q24) (no. 503) FISH revealed no rearrangement of the HMGA2 locus [39].…”

Section: Resultsmentioning

confidence: 96%

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Correlated Expression of HMGA2 and PLAG1 in Thyroid Tumors, Uterine Leiomyomas and Experimental Models

et al. 2014

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In pleomorphic adenomas of the salivary glands (PASG) recurrent chromosomal rearrangements affecting either 8q12 or 12q14∼15 lead to an overexpression of the genes of the genuine transcription factor PLAG1 or the architectural transcription factor HMGA2, respectively. Both genes are also affected by recurrent chromosomal rearrangements in benign adipocytic tumors as e. g. lipomas and lipoblastomas. Herein, we observed a strong correlation between the expression of HMGA2 and PLAG1 in 14 benign and 23 malignant thyroid tumors. To address the question if PLAG1 can be activated by HMGA2, the expression of both genes was quantified in 32 uterine leiomyomas 17 of which exhibited an overexpression of HMGA2. All leiomyomas with HMGA2 overexpression also revealed an activation of PLAG1 in the absence of detectable chromosome 8 abnormalities affecting the PLAG1 locus. To further investigate if the overexpression of PLAG1 is inducible by HMGA2 alone, HMGA2 was transiently overexpressed in MCF-7 cells. An increased PLAG1 expression was observed 24 and 48 h after transfection. Likewise, stimulation of HMGA2 by FGF1 in adipose tissue-derived stem cells led to a simultaneous increase of PLAG1 mRNA. Altogether, these data suggest that HMGA2 is an upstream activator of PLAG1. Accordingly, this may explain the formation of tumors as similar as lipomas and lipoblastomas resulting from an activation of either of both genes by chromosomal rearrangements.

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“…In the remaining case without elevated HMGA2 expression despite a cytogenetically visible t(12;14)(q15;q24) (no. 503) FISH revealed no rearrangement of the HMGA2 locus [39].…”

Section: Resultsmentioning

confidence: 96%

“…The remaining twelve tumors were follicular thyroid carcinomas (FTC). Cryopreserved tissue samples of 32 uterine leiomyomas that have been analyzed cytogenetically [16], [39]–[41], were also used for quantification of gene expression. The karyotypes of the leiomyomas are given in supplementary Table S1.…”

Section: Methodsmentioning

confidence: 99%

Correlated Expression of HMGA2 and PLAG1 in Thyroid Tumors, Uterine Leiomyomas and Experimental Models

et al. 2014

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“…In addition, an intragenic rearrangement of HMGA2 has been observed in a boy presenting with extreme somatic overgrowth (Ligon et al, 2005). Overexpression of HMGA2 due to chromosomal rearrangements is associated with the growth of a variety of benign tumors arising from mesenchyme-derived tissues as, e.g., adipose tissue, smooth muscle tissues, or cartilage (Ashar et al, 1995;Schoenmakers et al, 1995;Gross et al, 2003;Klemke et al, 2009). All these findings link HMGA2 with stem cell behavior, i.e., regulation of their self-renewal capacity.…”

Section: Discussionmentioning

confidence: 97%

p14^Arf acts as an antagonist of HMGA2 in senescence of mesenchymal stem cells—implications for benign tumorigenesis

Markowski

Winter

Meyer³

et al. 2011

Genes Chromosomes & Cancer

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HMGA2 is a major regulator of benign tumorigenesis from mesenchyme-derived tissues and stem-cell self-renewal. It has been postulated that HMGA2 mediates its critical function by decreasing p16(Ink4a)/p14(Arf) expression and cellular senescence. To repress the oncogenic activity of HMGA2, the lin-28-let-7 axis is thought to increasingly repress the expression of HMGA2 with age. To understand the HMGA2-p14(Arf) -relationship in benign tumorigenesis, we performed a series of experiments on mesenchymal stem-cells, i.e., the proposed cells of origin of lipomas and uterine leiomyomas. The expression of both genes was inversely correlated during senescence in vitro but contrary to the expectations in adipose tissue derived stem cells (ADSCs) stimulation of HMGA2 by FGF1 increased the expression of p14(Arf) . Based on the assumption that in ADSCs p14(Arf) is repressing HMGA2, siRNA silencing of p14(Arf) was performed resulting in a significant upregulation of HMGA2. To see if p14(Arf) can repress HMGA2 by a TP53-dependent mechanism, nutlin-3, a known MDM2 antagonist, was used which not only increased the activity of the senescence, associated markers p21 and beta-galactosidase, but also decreased the expression of HMGA2, suggesting that p14(Arf) indeed influences HMGA2 by a p53-dependent mechanism because nutlin-3 stabilizes p53. Accordingly, the HMGA2 response triggered by serum was reduced by treatment of ADSCs with nutlin-3. As to the interaction between HMGA2 and p14(Arf) in benign tumorigenesis, we propose a model where akin to MSC self-renewal during tissue repair the simultaneous increase of p14(Arf) with HMGA2 ensures genomic stability, whereas in turn p14(Arf) can repress HMGA2 via TP53.

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“…From tumor samples stored in Hank's solution, cell cultures were set up as described recently [29]. In brief, the tissue samples were minced into small pieces and treated with collagenase (200 U) for 4.5 to 6 h. Dissociated cells were centrifuged and resuspended in culture medium (RPMI 1640 supplemented with 20% FCS, 100 IU/ml penicillin and 100 μg/ml streptomycin).…”

Section: Methodsmentioning

confidence: 99%

Factors affecting the loss of MED12-mutated leiomyoma cells during in vitro growth

et al. 2017

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Uterine leiomyomas (UL) are the most prevalent symptomatic human tumors at all and somatic mutations of the gene encoding mediator subcomplex 12 (MED12) constitute the most frequent driver mutations in UL. Recently, a rapid loss of mutated cells during in vitro growth of UL-derived cell cultures was reported, resulting in doubts about the benefits of UL-derived cell cultures. To evaluate if the rapid loss of MED12-mutated cells in UL cell cultures depends on in vitro passaging, we set up cell cultures from nine UL from 40–50 year old Caucasian patients with at least one UL. Cultured UL cells were investigated for loss of MED12-mutated cells. Genetic characterization of native tumor samples and adjacent myometrium was done by array analysis. “Aged” primary cultures without passaging were compared to cells of three subsequent passages. Comparative analyses of the mutated/non-mutated ratios between native tissue, primary cells, and cultured tumor cells revealed a clear decrease of MED12-mutated cells. None of the tumors showed gross alterations of the array profiles, excluding the presence of gross genomic imbalances besides the MED12 mutations as a reason for the intertumoral variation in the loss of MED12-mutated cells. Albeit at a lesser rate, loss of MED12-mutated cells from cell cultures of UL occurs even without passaging thus indicating the requirement of soluble factors or matrix components lacking in vitro. Identification of these factors can help to understand the mechanisms of the growth of the most frequent type of uterine leiomyomas and to decipher novel drug targets.

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Overexpression of HMGA2 in uterine leiomyomas points to its general role for the pathogenesis of the disease

Cited by 58 publications

References 35 publications

Correlated Expression of HMGA2 and PLAG1 in Thyroid Tumors, Uterine Leiomyomas and Experimental Models

Correlated Expression of HMGA2 and PLAG1 in Thyroid Tumors, Uterine Leiomyomas and Experimental Models

p14^Arf acts as an antagonist of HMGA2 in senescence of mesenchymal stem cells—implications for benign tumorigenesis

Factors affecting the loss of MED12-mutated leiomyoma cells during in vitro growth

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Overexpression of HMGA2 in uterine leiomyomas points to its general role for the pathogenesis of the disease

Cited by 58 publications

References 35 publications

Correlated Expression of HMGA2 and PLAG1 in Thyroid Tumors, Uterine Leiomyomas and Experimental Models

Correlated Expression of HMGA2 and PLAG1 in Thyroid Tumors, Uterine Leiomyomas and Experimental Models

p14Arf acts as an antagonist of HMGA2 in senescence of mesenchymal stem cells—implications for benign tumorigenesis

Factors affecting the loss of MED12-mutated leiomyoma cells during in vitro growth

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p14^Arf acts as an antagonist of HMGA2 in senescence of mesenchymal stem cells—implications for benign tumorigenesis