Identification of novel HMGA2 fusion sequences in lipoma: Evidence that deletion of let‐7 miRNA consensus binding site 1 in the HMGA2 3′ UTR is not critical for HMGA2 transcriptional upregulation

Wang, Xiaoke; Hulshizer, Rachael L.; Erickson-Johnson, Michele R.; Flynn, Heather C.; Jenkins, Robert B.; Lloyd, Ricardo V.; Oliveira, André M.

doi:10.1002/gcc.20674

Cited by 14 publications

(11 citation statements)

References 22 publications

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“…The let-7/miR-98 targets that have been identified include RAS, MYC, HMGA2, IMP-1, CDC25A and CDK6. [27][28][29][30][31][32][33][34][35][36] Our solid results support that Fas is a new target of let-7/miR-98, which suggests let-7/ miR-98 is involved in Fas-mediated function.…”

Section: Resultssupporting

confidence: 57%

Let-7/miR-98 regulate Fas and Fas-mediated apoptosis

Tang

Cui

et al. 2011

Genes Immun

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Fas is ubiquitously expressed on a variety of cells and triggers apoptosis, which have critical roles in the immune system. MicroRNAs (miRNAs) have been recently identified as regulators that modulate target gene expression and are involved in diverse biological processes, such as cell proliferation and apoptosis. This study was undertaken to investigate the contribution of miRNA in the regulation of Fas expression and Fas-mediated apoptosis. Bioinformatics analysis indicated that Fas was a potential target of let-7/miR-98 family. Indeed ectopic expression of let-7/miR-98 reduced, whereas knockdown of endogenous let-7/miR-98 increased the expression of Fas at both mRNA and protein levels. Let-7/miR-98 was verified to target Fas 3 0 untranslated region directly by site-directed gene mutagenesis and reporter gene assay. More importantly, introduction of let-7/miR-98 could decrease the sensitivity to Fas-induced apoptosis. Furthermore, let-7/miR-98 expression was reduced in activation-induced cell death process, accompanied by increased expression of Fas. In conclusion, our study first demonstrated that let-7/miR-98 regulated Fas expression and the sensitivity of Fas-mediated apoptosis.

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Section: Resultssupporting

confidence: 57%

Let-7/miR-98 regulate Fas and Fas-mediated apoptosis

Tang

Cui

et al. 2011

Genes Immun

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“…The mechanism underlying this systematic loss or reduction of expression of the 3 0 UTR in lipomas overexpressing HMGA2 remains to be elucidated. Breakpoints in the 3 0 UTR have also been reported in lipomas (Schoenmakers et al, 1995;Wang et al, 2009). In the two cases described by Wang et al (2009), the breakpoints occurred between the let-7 consensus-binding sites (CBS) 1 and 2 allowing the authors to suggest that the elimination of let-7 CBS 1 was not critical for transcriptional upregulation of HMGA2.…”

Section: Hmga2 and Let-7 Expression In Adipocytic Tumorsmentioning

confidence: 86%

Let‐7 MicroRNA and HMGA2 levels of expression are not inversely linked in adipocytic tumors: Analysis of 56 lipomas and liposarcomas with molecular cytogenetic data

Bianchini¹,

Saâda²,

Gjernes³

et al. 2011

Genes Chromosomes & Cancer

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The aim of our study was first to assess the role of HMGA2 expression in the pathogenesis of adipocytic tumors (AT) and, second, to seek a potential correlation between overexpression of HMGA2 and let-7 expression inhibition by analyzing a series of 56 benign and malignant AT with molecular cytogenetic data. We measured the levels of expression of HMGA2 mRNA and of eight members of the let-7 microRNA family using quantitative RT-PCR and expression of HMGA2 protein using immunohistochemistry. HMGA2 was highly overexpressed in 100% of well-differentiated/dedifferentiated liposarcomas (WDLPS/DDLPS), all with HMGA2 amplification, and 100% of lipomas with HMGA2 rearrangement. Overexpression of HMGA2 mRNA was detected in 76% of lipomas without HMGA2 rearrangement. HMGA2 protein expression was detected in 100% of lipomas with HMGA2 rearrangement and 48% of lipomas without HMGA2 rearrangement. We detected decreased expression levels of some let-7 members in a significant proportion of AT. Notably, let-7b and let-7g were inhibited in 61% of WDLPS/DDLPS. In lipomas, each type of let-7 was inhibited in approximately one-third of the cases. Although overexpression of both HMGA2 mRNA and protein in a majority of ordinary lipomas without HMGA2 structural rearrangement may have suggested a potential role for let-7 microRNAs, we did not observe a significant link with let-7 inhibition in such cases. Our results indicate that inhibition of let-7 microRNA expression may participate in the deregulation of HMGA2 in AT but that this inhibition is neither a prominent stimulator for HMGA2 overexpression nor a surrogate to genomic HMGA2 rearrangements.

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“…Indeed, HMGA2 is overexpressed in a number of different types of human cancer, including lipoma and liposarcoma, where levels of HMGA2 are almost always elevated (49,66,67). In many of these cases, the 3= UTR of HMGA2 has been truncated, leading to dramatic overexpression.…”

Section: Mir-33b Expression Is Induced During Differentiation Of Humamentioning

confidence: 99%

SREBP-1c/MicroRNA 33b Genomic Loci Control Adipocyte Differentiation

Price

Holtrup

Kwei

et al. 2016

Molecular and Cellular Biology

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White adipose tissue (WAT) is essential for maintaining metabolic function, especially during obesity. The intronic microRNAs miR33a and miR-33b, located within the genes encoding sterol regulatory element-binding protein 2 (SREBP-2) and SREBP-1, respectively, are transcribed in concert with their host genes and function alongside them to regulate cholesterol, fatty acid, and glucose metabolism. SREBP-1 is highly expressed in mature WAT and plays a critical role in promoting in vitro adipocyte differentiation. It is unknown whether miR-33b is induced during or involved in adipogenesis. This is in part due to loss of miR-33b in rodents, precluding in vivo assessment of the impact of miR-33b using standard mouse models. This work demonstrates that miR-33b is highly induced upon differentiation of human preadipocytes, along with SREBP-1. We further report that miR-33b is an important regulator of adipogenesis, as inhibition of miR-33b enhanced lipid droplet accumulation. Conversely, overexpression of miR-33b impaired preadipocyte proliferation and reduced lipid droplet formation and the induction of peroxisome proliferator-activated receptor ␥ (PPAR␥) target genes during differentiation. These effects may be mediated by targeting of HMGA2, cyclin-dependent kinase 6 (CDK6), and other predicted miR-33b targets. Together, these findings demonstrate a novel role of miR-33b in the regulation of adipocyte differentiation, with important implications for the development of obesity and metabolic disease.O besity is one of the largest burdens on the health care systems of developed countries and is a major risk factor in the development of insulin resistance, dyslipidemia, and hypertension, leading to a condition known as metabolic syndrome (1). However, obesity is not always associated with metabolic syndrome, as in the case of mice overexpressing adiponectin (2). On an ob/ob background, these mice have dramatically increased adipose tissue mass, but this does not promote insulin resistance, as the mice actually have improved insulin sensitivity. Alternatively, lipodystrophy, a condition caused by mutations that impair the expansion or differentiation of white adipose tissue (WAT), leads to severe forms of metabolic syndrome (3). Overall, the association between both impaired and excessive WAT accumulation and the development of metabolic syndrome emphasizes the critical role of WAT in maintaining metabolic homeostasis.Recent work has demonstrated an important role for WAT in regulating whole-body metabolism through the release of signaling molecules, such as leptin and adiponectin, which can regulate insulin sensitivity and appetite regulation in other tissues. Moreover, it has been known for some time that an inability of WAT to properly remove and store circulating lipids results in accumulation of lipids in nonadipose tissues, promoting diseases such as type II diabetes and atherosclerosis (4,5). De novo lipid biosynthesis is controlled by sterol regulatory element-binding proteins (SREBPs), which are activated in resp...

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Identification of novel HMGA2 fusion sequences in lipoma: Evidence that deletion of let‐7 miRNA consensus binding site 1 in the HMGA2 3′ UTR is not critical for HMGA2 transcriptional upregulation

Cited by 14 publications

References 22 publications

Let-7/miR-98 regulate Fas and Fas-mediated apoptosis

Let-7/miR-98 regulate Fas and Fas-mediated apoptosis

Let‐7 MicroRNA and HMGA2 levels of expression are not inversely linked in adipocytic tumors: Analysis of 56 lipomas and liposarcomas with molecular cytogenetic data

SREBP-1c/MicroRNA 33b Genomic Loci Control Adipocyte Differentiation

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