Posttranscriptional deregulation of signaling pathways in meningioma subtypes by differential expression of miRNAs

Ludwig, Nicole; Kim, Yoo-Jin; Mueller, Sabine C.; Backes, Christina; Werner, Tamara V.; Galata, Valentina; Sartorius, Elke; Bohle, Rainer M.; Keller, Andreas; Meese, Eckart

doi:10.1093/neuonc/nov014

Cited by 33 publications

(52 citation statements)

References 47 publications

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“…Among putative target genes of deregulated miRNAs are Wnt pathway genes and genes involved in epithelial‐to‐mesenchymal transition (Ludwig et al . ).…”

Section: Discussionmentioning

confidence: 97%

“…As indicated by novel research, epigenetic events also play important roles in meningioma (Murny ak et al 2015); for example, differential expression of miRNAs post-transcriptionally deregulates many signalling pathways in meningioma. Among putative target genes of deregulated miRNAs are Wnt pathway genes and genes involved in epithelial-to-mesenchymal transition (Ludwig et al 2015).…”

Section: Figurementioning

confidence: 99%

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Loss of p53 expression is accompanied by upregulation of beta‐catenin in meningiomas: a concomitant reciprocal expression

Pećina‐Šlaus

Kafka

Vladušić

et al. 2016

Int J Experimental Path

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Crosstalk between Wnt and p53 signalling pathways in cancer has long been suggested. Therefore in this study we have investigated the involvement of these pathways in meningiomas by analysing their main effector molecules, beta-catenin and p53. Cellular expression of p53 and beta-catenin proteins and genetic changes in TP53 were analysed by immunohistochemistry, PCR/RFLP and direct sequencing of TP53 exon 4. All the findings were analysed statistically. Our analysis showed that 47.5% of the 59 meningiomas demonstrated loss of expression of p53 protein. Moderate and strong p53 expression in the nuclei was observed in 8.5% and 6.8% of meningiomas respectively. Gross deletion of TP53 gene was observed in one meningioma, but nucleotide alterations were observed in 35.7% of meningiomas. In contrast, beta-catenin, the main Wnt signalling molecule, was upregulated in 71.2%, while strong expression was observed in 28.8% of meningiomas. The concomitant expressions of p53 and beta-catenin were investigated in the same patients. In the analysed meningiomas, the levels of the two proteins were significantly negatively correlated (P = 0.002). This indicates that meningiomas with lost p53 upregulate beta-catenin and activate Wnt signalling. Besides showing the reciprocal relationship between proteins, we also showed that the expression of p53 was significantly (P = 0.021) associated with higher meningioma grades (II and III), while beta-catenin upregulation was not associated with malignancy grades. Additionally, women exhibited significantly higher values of p53 loss when compared to males (P = 0.005). Our findings provide novel information about p53 involvement in meningeal brain tumours and reveal the complex relationship between Wnt and p53 signalling, they suggest an important role for beta-catenin in these tumours.

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“…Among putative target genes of deregulated miRNAs are Wnt pathway genes and genes involved in epithelial‐to‐mesenchymal transition (Ludwig et al . ).…”

Section: Discussionmentioning

confidence: 97%

Section: Figurementioning

confidence: 99%

Loss of p53 expression is accompanied by upregulation of beta‐catenin in meningiomas: a concomitant reciprocal expression

Pećina‐Šlaus

Kafka

Vladušić

et al. 2016

Int J Experimental Path

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“…In our previous studies, we highlighted the central role of miR-34a in T cell receptor signaling via regulation of five PKC family members [31]. MiR-34a is dys-regulated in numerous tumors types like cancers of brain, lung, pancreas, colon, esophagus, and liver [32][33][34][35][36][37][38]. As a tumor suppressor miRNA, miR-34a regulates a variety of oncogenic targets genes, for example MET proto-oncogene (MET), sirtuin 1 (SIRT1), Notch-1 and CD44 molecule (CD44) [39][40][41][42][43].…”

Section: Introductionmentioning

confidence: 99%

The deterministic role of 5-mers in microRNA-gene targeting

et al. 2018

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MiRNAs play a central role in physiological and pathological processes. Both for the biological understanding and for their clinical application, it is essential to understand the interaction of miRNAs and their targets. Target identification largely hinges on in-silico prediction, which requires a complete consideration of miRNA binding sites within the UTRs of target genes. Here, we show that 5-mer sites might also play an essential role for human miRNA-target binding. We implemented and employed an algorithm to all pairs of 2,588 human miRNAs annotated in miRBase and the 3' UTRs of 16725 genes (>43 million combinations). Our in-silico analysis showed a highly significant enrichment (p = 1.4 × 10) of 5-mer binding sites in 3' UTRs across all experimentally validated miRNA-target gene pairs. We next confirmed the central role of 5-mer binding sites by reporter assays and demonstrated that two non-canonical 5-mer sites of miR-34a in the 3' UTR of T-cell receptor alpha (TCRA) have a significantly stronger influence on its posttranscriptional regulation than the canonical binding sites. These observations indicate an essential role of 5-mer binding sites for the miRNA targeting in human cells.

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“…By contrast, the downstream effects of miR-34a-3p, which is downregulated in higher-grade meningiomas [13], are less well elucidated. It is, however, known that both the miR-34a-5p and the miR-34a-3p, which are derived from the pre-miR-34a, are active [17].…”

Section: Introductionmentioning

confidence: 99%

MiR-34a-3p alters proliferation and apoptosis of meningioma cells in vitro and is directly targeting SMAD4, FRAT1 and BCL2

Werner

Hart

Nickels

et al. 2017

Aging

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Micro (mi)RNAs are short, noncoding RNAs and deregulation of miRNAs and their targets are implicated in tumor generation and progression in many cancers. Meningiomas are mostly benign, slow growing tumors of the central nervous system with a small percentage showing a malignant phenotype.Following in silico prediction of potential targets of miR-34a-3p, SMAD4, FRAT1, and BCL2 have been confirmed as targets by dual luciferase assays with co-expression of miR-34a-3p and reporter gene constructs containing the respective 3'UTRs. Disruption of the miR-34a-3p binding sites in the 3'UTRs resulted in loss of responsiveness to miR-34a-3p overexpression. In meningioma cells, overexpression of miR-34a-3p resulted in decreased protein levels of SMAD4, FRAT1 and BCL2, while inhibition of miR-34a-3p led to increased levels of these proteins as confirmed by Western blotting. Furthermore, deregulation of miR-34a-3p altered cell proliferation and apoptosis of meningioma cells in vitro.We show that SMAD4, FRAT1 and BCL2 are direct targets of miR-34a-3p and that deregulation of miR-34a-3p alters proliferation and apoptosis of meningioma cells in vitro. As part of their respective signaling pathways, which are known to play a role in meningioma genesis and progression, deregulation of SMAD4, FRAT1 and BCL2 might contribute to the aberrant activation of these signaling pathways leading to increased proliferation and inhibition of apoptosis in meningiomas.

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Posttranscriptional deregulation of signaling pathways in meningioma subtypes by differential expression of miRNAs

Cited by 33 publications

References 47 publications

Loss of p53 expression is accompanied by upregulation of beta‐catenin in meningiomas: a concomitant reciprocal expression

Loss of p53 expression is accompanied by upregulation of beta‐catenin in meningiomas: a concomitant reciprocal expression

The deterministic role of 5-mers in microRNA-gene targeting

MiR-34a-3p alters proliferation and apoptosis of meningioma cells in vitro and is directly targeting SMAD4, FRAT1 and BCL2

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