A <i>Pitx2</i>-MicroRNA Pathway Modulates Cell Proliferation in Myoblasts and Skeletal-Muscle Satellite Cells and Promotes Their Commitment to a Myogenic Cell Fate

Lozano-Velasco, Estefanía; Vallejo, Daniel; Esteban, Francisco J.; Doherty, Chris; Hernández-Torres, Francisco; Franco, Diego; Aránega, Amelia

doi:10.1128/mcb.00536-15

Cited by 47 publications

(50 citation statements)

References 61 publications

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“…In accordance, upregulation of miR-106b was correlated with a significant enrichment of known miR-106b target genes and recent studies suggest a tumor suppressor function for miR-106b. 31,32 To identify patients who might achieve an enduring reversal of the aberrant epigenetic state and who would likely benefit from VPA treatment in addition to chemotherapy, we delineated a 9-gene VPA response predictor comprising genes directly affected by VPA in vitro and in vivo treatment. Of these, deregulated CXCR4 and LBH expression have been associated with solid tumors and leukemias, 33,34 and therefore we investigated their expression and prognostic impact in an independent cohort of 114 VPA treated primary AMLs.…”

Section: Discussionmentioning

confidence: 99%

Molecular dissection of valproic acid effects in acute myeloid leukemia identifies predictive networks

et al. 2016

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2016) Molecular dissection of valproic acid effects in acute myeloid leukemia identifies predictive networks, Epigenetics, 11:7, 517-525, ABSTRACTHistone deacetylase inhibitors (HDACIs) like valproic acid (VPA) display activity in leukemia models and induce tumor-selective cytotoxicity against acute myeloid leukemia (AML) blasts. As there are limited data on HDACIs effects, we aimed to dissect VPA effects in vitro using myeloid cell lines with the idea to integrate findings with in vivo data from AML patients treated with VPA additionally to intensive chemotherapy (n D 12). By gene expression profiling we identified an in vitro VPA response signature enriched for genes/pathways known to be implicated in cell cycle arrest, apoptosis, and DNA repair. Following VPA treatment in vivo, gene expression changes in AML patients showed concordant results with the in vitro VPA response despite concomitant intensive chemotherapy. Comparative miRNA profiling revealed VPA-associated miRNA expression changes likely contributing to a VPA-induced reversion of deregulated gene expression. In addition, we were able to define markers predicting VPA response in vivo such as CXCR4 and LBH. These could be validated in an independent cohort of VPA and intensive chemotherapy treated AML patients (n D 114) in which they were inversely correlated with relapse-free survival. In summary, our data provide new insights into the molecular mechanisms of VPA in myeloid blasts, which might be useful in further advancing HDAC inhibition based treatment approaches in AML.

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Section: Discussionmentioning

confidence: 99%

Molecular dissection of valproic acid effects in acute myeloid leukemia identifies predictive networks

et al. 2016

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“…71 PITX2, belonging to the RIEG/PITX homeobox family, is involved in control of cell proliferation and morphogenesis. 72,73 PITX2 is associated with Wnt and transforming growth factor (TGF)-beta signaling and is hypermethylated in breast, prostate, and may other cancers. Hypermethylation of PITX2 is associated with poor survival in breast cancer, and it is a prognostic marker of biochemical recurrence in prostate cancer.…”

Section: Discussionmentioning

confidence: 99%

Aberrant gene-specific DNA methylation signature analysis in cervical cancer

et al. 2017

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Multicomponent molecular modifications such as DNA methylation may offer sensitive and specific cervical intraepithelial neoplasia and cervical cancer biomarkers. In this study, we tested cervical tissues at various stages of tumor progression for 5-methylcytosine and 5-hydroxymethylcytosine levels and also DNA promoter methylation profile of a panel of genes for its diagnostic potential. In total, 5-methylcytosine, 5-hydroxymethylcytosine, and promoter methylation of 33 genes were evaluated by reversed-phase high-performance liquid chromatography, enzyme-linked immunosorbent assay based technique, and bisulfate-based next generation sequencing. The 5-methylcytosine and 5-hydroxymethylcytosine contents were significantly reduced in squamous cell carcinoma and receiver operating characteristic curve analysis showed a significant difference in (1) 5-methylcytosine between normal and squamous cell carcinoma tissues (area under the curve = 0.946) and (2) 5-hydroxymethylcytosine levels among normal, squamous intraepithelial lesions and squamous cell carcinoma. Analyses of our next generation sequencing results and data from five independent published studies consisting of 191 normal, 10 low-grade squamous intraepithelial lesions, 21 high-grade squamous intraepithelial lesions, and 335 malignant tissues identified a panel of nine genes (ARHGAP6, DAPK1, HAND2, NKX2-2, NNAT, PCDH10, PROX1, PITX2, and RAB6C) which could effectively discriminate among the various groups with sensitivity and specificity of 80%-100% (p < 0.05). Furthermore, 12 gene promoters (ARHGAP6, HAND2, LHX9, HEY2, NKX2-2, PCDH10, PITX2, PROX1, TBX3, IKBKG, RAB6C, and DAPK1) were also methylated in one or more of the cervical cancer cell lines tested. The global and gene-specific methylation of the panel of genes identified in our study may serve as useful biomarkers for the early detection and clinical management of cervical cancer.

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“…This data indicated that in fact the majority of the altered intronic miRNAs had their proper promoters under the control of specific transcription factors, which might be altered in AF. In line with this hypothesis, promoter hypermethylation of Pitx2 [ 39 ] is associated with its down-regulation in LA from patients with AF [ 55 ], and could explain the down-regulation of miR-133a ( S3 Table ), which is under PITX2 control [ 56 ]. Moreover during the past decade, a number of mutations in transcription factors have been reported to underlie congenital heart diseases associated with structural cardiac defects [ 57 – 59 ].…”

Section: Resultsmentioning

confidence: 98%

Analysis of the microRNA signature in left atrium from patients with valvular heart disease reveals their implications in atrial fibrillation

et al. 2018

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BackgroundAmong the potential factors which may contribute to the development and perpetuation of atrial fibrillation, dysregulation of miRNAs has been suggested. Thus in this study, we have quantified the basal expressions of 662 mature human miRNAs in left atrium (LA) from patients undergoing cardiac surgery for valve repair, suffering or not from atrial fibrillation (AF) by using TaqMan® Low Density arrays (v2.0).ResultsAmong the 299 miRNAs expressed in all patients, 42 miRNAs had altered basal expressions in patients with AF. Binding-site predictions with Targetscan (conserved sites among species) indicated that the up- and down-regulated miRNAs controlled respectively 3,310 and 5,868 genes. To identify the most relevant cellular functions under the control of the altered miRNAs, we focused on the 100 most targeted genes of each list and identified 5 functional protein-protein networks among these genes. Up-regulated networks were involved in synchronisation of circadian rythmicity and in the control of the AKT/PKC signaling pathway (i.e., proliferation/adhesion). Down-regulated networks were the IGF-1 pathway and TGF-beta signaling pathway and a network involved in RNA-mediated gene silencing, suggesting for the first time that alteration of miRNAs in AF would also perturbate the whole miRNA machinery. Then we crossed the list of miRNA predicted genes, and the list of mRNAs altered in similar patients suffering from AF and we found that respectively 44.5% and 55% of the up- and down-regulated mRNA are predicted to be conserved targets of the altered miRNAs (at least one binding site in 3’-UTR). As they were involved in the same biological processes mentioned above, these data demonstrated that a great part of the transcriptional defects previously published in LA from AF patients are likely due to defects at the post-transcriptional level and involved the miRNAs.ConclusionsOur stringent analysis permitted us to identify highly targeted protein-protein networks under the control of miRNAs in LA and, among them, to highlight those specifically affected in AF patients with altered miRNA signature. Further studies are now required to determine whether alterations of miRNA levels in AF pathology are causal or represent an adaptation to prevent cardiac electrical and structural remodeling.

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A Pitx2-MicroRNA Pathway Modulates Cell Proliferation in Myoblasts and Skeletal-Muscle Satellite Cells and Promotes Their Commitment to a Myogenic Cell Fate

Cited by 47 publications

References 61 publications

Molecular dissection of valproic acid effects in acute myeloid leukemia identifies predictive networks

Molecular dissection of valproic acid effects in acute myeloid leukemia identifies predictive networks

Aberrant gene-specific DNA methylation signature analysis in cervical cancer

Analysis of the microRNA signature in left atrium from patients with valvular heart disease reveals their implications in atrial fibrillation

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