PDF(Pubmed)
Abstract：
Glioblastoma (GBM) is one of the most frequent primary brain tumors. Limited therapeutic options and high recurrency rates lead to a dismal prognosis. One frequent, putative driver mutation is the genomic amplification of the oncogenic receptor tyrosine kinase EGFR. Often accompanied by variants like EGFRvIII, heterogenous expression and ligand independent signaling render this tumor subtype even more difficult to treat, as EGFR-directed therapeutics show only weak effects at best. So EGFR-amplified GBM is considered to have an even worse prognosis, and therefore, deeper understanding of molecular mechanisms and detection of potential targets for novel therapeutic strategies is urgently needed. In this study, we looked at the level of microRNAs (miRs), small non-coding RNAs frequently deregulated in cancer, both acting as oncogenes and tumor suppressors. Comparative analysis of GBM with and without EGFR amplification should give insight into the expression profiles of miRs, which are considered both as potential targets for directed therapies or as therapeutic reagents. Comparison of miR profiles of EGFR-amplified and EGFR-normal GBM revealed an upregulation of the miR-183/96/182 cluster, which is associated with oncogenic properties in several tumor entities. One prominent target of this miR cluster is FOXO1, a pro-apoptotic factor. By observing FOXO1 downregulation in EGFR-amplified tumors, we can see a significant correlation of EGFR amplification, miR-183/96/182 cluster upregulation, and repression of FOXO1. Although no significant difference in overall survival is shown, these data may contribute to the molecular understanding of this tumor subtype and offer potential targets for miR-based therapies.
摘要：
胶质母细胞瘤(GBM)是最常见的原发性脑肿瘤之一。有限的治疗选择和高复发率导致预后不良。一个频繁的,推定的驱动突变是致癌受体酪氨酸激酶EGFR的基因组扩增.通常伴有EGFRvIII等变体，异源表达和不依赖配体的信号使这种肿瘤亚型更加难以治疗，因为EGFR定向疗法最多只能显示微弱的效果。所以EGFR扩增的GBM被认为预后更差，因此,我们迫切需要更深入地了解新的治疗策略的分子机制和潜在靶点的检测.在这项研究中,我们观察了microRNAs（miRs）的水平，小的非编码RNA经常在癌症中失调，既充当癌基因又充当肿瘤抑制因子。有和没有EGFR扩增的GBM的比较分析应该深入了解miR的表达谱。它们既被认为是定向治疗的潜在靶标，也被认为是治疗试剂。EGFR扩增和EGFR正常GBM的miR谱的比较揭示了miR-183/96/182簇的上调,这与几种肿瘤实体的致癌特性有关。该miR簇的一个突出靶标是促凋亡因子FOXO1。通过观察FOXO1在EGFR扩增肿瘤中的下调，我们可以看到EGFR扩增的显著相关性，miR-183/96/182簇上调，以及对FOXO1的镇压。虽然在总生存率上没有显著差异,这些数据可能有助于对该肿瘤亚型的分子理解,并为基于miR的治疗提供潜在靶点.
