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首页> 外文期刊>Journal of experimental & clinical cancer research : >Empty spiracles homeobox genes EMX1 and EMX2 regulate WNT pathway activation in sarcomagenesis
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Empty spiracles homeobox genes EMX1 and EMX2 regulate WNT pathway activation in sarcomagenesis

机译：空螺旋Homeobox基因EMX1和EMX2调节SARComagenesis中的WNT途径激活

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Sarcomas are a very heterogeneous group of tumors with intrinsic developmental programs derived from the cell of origin. This implies a functional hierarchy inside tumors governed by sarcoma stem cells. Therefore, genetic and/or epigenetic changes profoundly affect the biology of sarcoma tumor stem cells. EMX genes are proposed to be transcription factors that are involved in the sarcomagenesis process, regardless of the neural or mesodermal embryological sarcoma origin. It has been shown that EMX1 or EMX2 overexpression reduces tumorigenic properties, while reducing the levels of these genes enhances these properties. Furthermore, it has been shown that EMX genes decrease the expression of stem cell regulatory genes and the stem cell phenotype. Taken together, these results indicate that the EMX1 and EMX2 genes negatively regulate these tumor-remodeling populations or sarcoma stem cells, acting as tumor suppressors in sarcoma. Bioinformatic analysis, quantitative mRNA and protein expression analysis, cell models of sarcoma by ectopic expression of EMX genes. By cell biology methods we measured tumorigenesis and populations enriched on stem cell phenotypes, either in vitro or in vivo. In this work, we showed that the canonical Wnt pathway is one of the mechanisms that explains the relationships of EMX1/EMX2 and stem cell genes in sarcoma. The Wnt-EMX1/EMX2 relationship was validated in silico with sarcoma patient datasets, in vitro in primary derived sarcoma cell lines, and in vivo. EMX expression was found to negatively regulate the Wnt pathway. In addition, the constitutive activation of the Wnt pathway revers to a more aggressive phenotype with stem cell properties, and stemness gene transcription increased even in the presence of EMX1 and/or EMX2 overexpression, establishing the relationship among the Wnt pathway, stem cell genes and the EMX transcription factors. Our data showed that Empty Spiracles Homeobox Genes EMX1 and EMX2 represses WNT signalling and activation of WNT pathway bypass EMX-dependent stemness repression and induces sarcomagenesis. These results also suggest the relevance of the Wnt/b-catenin/stemness axis as a therapeutic target in sarcoma.
机译：Sarcomas是一种非常异质的肿瘤，具有来自原产地的内在发育计划。这意味着由肉瘤干细胞治理的肿瘤内的功能性等级。因此，遗传和/或表观遗传变化深刻地影响肉瘤肿瘤干细胞的生物学。 eMX基因被提出为涉及SARComagenesis过程的转录因子，无论神经或中胚层胚胎肉瘤起源如何。已经表明，EMX1或EMX2过表达降低了致瘤性质，同时降低了这些基因的水平，增强了这些性质。此外，已经表明EMX基因降低干细胞调节基因的表达和干细胞表型。总之，这些结果表明，EMX1和EMX2基因对这些肿瘤重塑群体或肉瘤干细胞产生负面调节，作为肉瘤中的肿瘤抑制剂。生物信息分析，定量mRNA和蛋白质表达分析，肉瘤的细胞模型通过EMX基因的异位表达。通过细胞生物学方法，我们测量肿瘤发生和富含干细胞表型的血液鉴定和体外体内的血液瘤。在这项工作中，我们表明规范WNT途径是解释肉瘤中EMX1 / EMX2和干细胞基因的关系的机制之一。 WNT-EMX1 / EMX2的关系在硅中验证了肉瘤患者数据集，在主要衍生的肉瘤细胞系中体外，体内。发现EMX表达对WNT途径产生负面调节。此外，即使在EMX1和/或EMX2过表达的情况下，也增加了WNT途径转化为具有干细胞性质的更具侵袭性表型的致病性表型，并且茎基因转录增加，建立了WNT途径，干细胞基因和EMX转录因子。我们的数据显示，空螺旋毒轴基因EMX1和EMX2抑制了WNT信号传导和激活WNT途径旁路EMX依赖性茎，诱导SARComagenesis。这些结果还表明Wnt / B-catenin /茎轴度轴与肉瘤中治疗靶标的相关性。

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