Frequent HRK inactivation associated with low apoptotic index in secondary glioblastomas
Frequent HRK inactivation associated with low apoptotic index in secondary glioblastomas
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DOI：
10.1007/s00401-005-1065-x
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发表时间：
2005-10-01
影响因子：
12.7
通讯作者：
Konishi, N
中科院分区：
文献类型：
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作者：
Nakamura, M;Ishida, E;Konishi, N
为了检测和识别人类胶质母细胞瘤中HRK基因的遗传改变和甲基化状态，我们分析了一组星形细胞肿瘤的超甲基化、12q13.1杂合性缺失和基因表达。我们的研究包括36例弥漫性低级别星形细胞瘤、32例间变性星形细胞瘤、64例原发性胶质母细胞瘤和28例继发性胶质母细胞瘤，后者由24例弥漫性低级别星形细胞瘤或4例间变性星形细胞瘤演变而来。HRK转录起始位点周围区域甲基化的弥漫性星形细胞瘤为19%，间变性星形细胞瘤为22%，原发性胶质母细胞瘤为27%，继发性胶质母细胞瘤为43%。与其他类型的肿瘤相比，61%的继发性胶质母细胞瘤中HRK表达显著降低，异常甲基化与表达缺失密切相关。逆转录-PCR分析也表明了一个明确的协议之间减少HRK蛋白水平和低或缺乏HRK转录。HRK免疫反应性的缺乏与低凋亡指数显著相关，而甲基化状态和凋亡之间的强相关性仅在继发性胶质母细胞瘤中发现。在星形细胞肿瘤中检测到HRK的异常甲基化，同时检测到多个基因的甲基化，包括p16（INK 4a）和p14（ARF）。有趣的是，继发性胶质母细胞瘤的这些表观遗传变化进一步与野生型p53相关。我们的研究结果表明，HRK失活主要是由异常的DNA甲基化在星形细胞肿瘤和HRK表达减少，有助于在高级别肿瘤的凋亡控制的损失。HRK表达降低可能是胶质母细胞瘤继发性发展的一个重要分子机制。
To detect and identify the genetic alterations and methylation status of the HRK gene in human glioblastomas, we analyzed a cohort of astrocytic tumors for hypermethylation, loss of heterozygosity on 12q13.1, and gene expression. Our study examined a series of 36 diffuse low-grade astrocytomas, 32 anaplastic astrocytomas, 64 primary glioblastomas, and 28 secondary glioblastomas that had evolved from either 24 low-grade diffuse astrocytomas or 4 anaplastic astrocytomas. The region around the HRK transcription start site was methylated in 19% of diffuse astrocytomas, in 22% of anaplastic astrocytomas, in 27% of primary glioblastomas, and in 43% of secondary glioblastomas. HRK expression was significantly reduced in 61% of secondary glioblastomas as compared to other types of tumors, and aberrant methylation was closely associated with loss of expression. Reverse transcription-PCR analysis also demonstrated a clear agreement between reduced HRK protein levels and low or absent HRK transcripts. Lack of HRK immunoreactivity was significantly correlated with a low apoptotic index, whereas a strong association between methylation status and apoptosis was found only in secondary glioblastomas. Abnormal methylation of HRK was detected in astrocytic tumors concurrent with methylation of multiple genes, including p16(INK4a) and p14(ARF). Interestingly, these epigenetic changes in secondary glioblastoma were further associated with wild-type p53. Our findings suggest that HRK is inactivated mainly by aberrant DNA methylation in astrocytic tumors and that reduced HRK expression contributes to the loss of apoptotic control in high-grade tumors. Reduced expression of HRK may serve as one important molecular mechanism in progression to secondary glioblastoma.