Detection of proneural/mesenchymal marker expression in glioblastoma: temporospatial dynamics and association with chromatin-modifying gene expression
Detection of proneural/mesenchymal marker expression in glioblastoma: temporospatial dynamics and association with chromatin-modifying gene expression
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DOI：
10.1007/s11060-015-1886-y
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发表时间：
2015-10-01
影响因子：
3.9
通讯作者：
Iihara, Koji
中科院分区：
文献类型：
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作者：
Murata, Hideki;Yoshimoto, Koji;Iihara, Koji
前神经和间质是通过基因表达谱鉴定的胶质母细胞瘤的两种亚型。本研究的主要目的是检测标志物，以建立一种临床上适用的方法来区分前神经胶质母细胞瘤和间叶胶质母细胞瘤。第二个目的是调查这些标记的时空动态，并探讨这些标记和染色质修饰基因的表达之间的关联。分析了133个胶质瘤样本（II级：14个样本，III级：18个，IV级：101个）。我们通过定量逆转录-聚合酶链反应定量了6个与前神经和间叶胶质母细胞瘤相关的特征基因的表达。我们根据6种标记物的平均值分配前神经（PN）和间充质（MES）评分，并通过从PN评分中减去MES来计算主要多基因（P-M）评分。我们使用这些评分来分析与恶性转化、肿瘤复发、肿瘤异质性、染色质修饰基因表达和HDAC7表达的相关性。MES评分与肿瘤分级呈正相关，而PN评分与肿瘤分级无关。P-M评分能够区分前神经和间质亚型。在肿瘤复发和恶性转化的情况下，它降低，并显示肿瘤内的变异性，表明肿瘤内的异质性。PN评分与多种组蛋白修饰基因的表达相关，而MES评分仅与HDAC7表达相关。因此，我们证明了一种简单直接的方法定量神经胶质母细胞瘤中的前神经/间充质标志物。值得注意的是，HDAC7表达可能是胶质母细胞瘤治疗中的新的治疗靶点。
Proneural and mesenchymal are two subtypes of glioblastoma identified by gene expression profiling. In this study, the primary aim was to detect markers to develop a clinically applicable method for distinguishing proneural and mesenchymal glioblastoma. The secondary aims were to investigate the temporospatial dynamics of these markers and to explore the association between these markers and the expression of chromatin-modifying genes. One hundred thirty-three glioma samples (grade II: 14 samples, grade III: 18, grade IV: 101) were analyzed. We quantified the expression of 6 signature genes associated with proneural and mesenchymal glioblastoma by quantitative reverse transcription-polymerase chain reaction. We assigned proneural (PN) and mesenchymal (MES) scores based on the average of the 6 markers and calculated a predominant metagene (P-M) score by subtracting the MES from the PN score. We used these scores to analyze correlations with malignant transformation, tumor recurrence, tumor heterogeneity, chromatin-modifying gene expression, and HDAC7 expression. The MES score positively correlated with tumor grade, whereas the PN score did not. The P-M score was able to distinguish the proneural and mesenchymal subtypes. It was decreased in cases of tumor recurrence and malignant transformation and showed variability within a tumor, suggesting intratumoral heterogeneity. The PN score correlated with the expression of multiple histone-modifying genes, whereas the MES score was associated only with HDAC7 expression. Thus, we demonstrated a simple and straightforward method of quantifying proneural/mesenchymal markers in glioblastoma. Of note, HDAC7 expression might be a novel therapeutic target in glioblastoma treatment.