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Assessment of PDGFRβ promoter methylation in canine osteosarcoma using methylation-sensitive high-resolution melting analysis.
Veterinary and Comparative Oncology ( IF 2.1 ) Pub Date : 2020-01-16 , DOI: 10.1111/vco.12567
Fabio Gentilini 1 , Ombretta Capitani 1 , Debora Tinto 1 , Antonella Rigillo 1 , Silvia Sabattini 1 , Giuliano Bettini 1 , Elena Turba Maria 2
Affiliation  

Platelet‐derived growth factor signalling pathways play a fundamental role in inducing and sustaining the proliferative and prosurvival stimuli in canine osteosarcomas (cOSAs). The increased expression of platelet‐derived growth factor receptors (PDGFRs) α and β, and their cognate ligands, were almost invariably observed in cOSAs and OSA‐derived cell lines. In particular, overexpression of PDGFRβ‐mediated signalling pathways was found in both the tumour microenvironment, where it drives stromal cell recruitment, and in neoangiogenesis, such as in tumour cells where it triggers aberrant proliferation, migration and local invasion. The majority of the pathological consequences of PDGFRβ signalling are because of aberrant expression. In fact, epigenetic dysregulation of oncogenes throughout demethylation of their promoter has emerged as a pivotal mechanism driving oncogenesis. The aim of this study was to assess the methylation status of the PDGFRβ promoter and to clarify its role in modulating the expression of the tyrosine kinase receptor in canine osteosarcoma. The CpG island of the PDGFRβ promoter was identified using a mixed in silico and experimental approach, and a method based upon the methylation‐sensitive high‐resolution melting assay for quantitatively and precisely assessing the methylation status of the promoter was then set up. The method herein described was then exploited to assess the methylation status of the promoter in a case series of cOSAa. COSAs consistently but variably expressed PDGFRβ. However, the promoter was almost completely demethylated, and its methylation status did not correlate with the expression levels. This finding supported the hypothesis that post‐transcriptional regulatory mechanisms may act in cOSAs.

中文翻译:

使用甲基化敏感的高分辨率熔解分析评估犬骨肉瘤中的 PDGFRβ 启动子甲基化。

血小板衍生的生长因子信号通路在诱导和维持犬骨肉瘤 (cOSA) 的增殖和促存活刺激方面发挥着重要作用。血小板衍生生长因子受体 (PDGFR) α 和 β 及其同源配体的表达增加,几乎总是在 cOSA 和 OSA 衍生细胞系中观察到。特别是,在肿瘤微环境中发现了 PDGFRβ 介导的信号通路的过度表达,在那里它驱动基质细胞募集,在新血管生成中,例如在肿瘤细胞中,它触发异常增殖、迁移和局部侵袭。PDGFRβ 信号传导的大部分病理结果是由于异常表达。实际上,癌基因在其启动子去甲基化过程中的表观遗传失调已成为驱动癌发生的关键机制。本研究的目的是评估甲基化状态PDGFRβ启动子并阐明其在调节犬骨肉瘤中酪氨酸激酶受体表达中的作用。PDGFRβ的 CpG 岛使用混合计算机和实验方法鉴定启动子,然后建立了一种基于甲基化敏感高分辨率熔解测定的方法,用于定量和精确评估启动子的甲基化状态。然后利用本文描述的方法来评估cOSAa病例系列中启动子的甲基化状态。COSA 始终如一地表达 PDGFRβ。然而,启动子几乎完全去甲基化,其甲基化状态与表达水平无关。这一发现支持了转录后调控机制可能在 cOSA 中起作用的假设。
更新日期:2020-01-16
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