Decreased expression of germinal center-associated nuclear protein is involved in chromosomal instability in malignant gliomas
Decreased expression of germinal center-associated nuclear protein is involved in chromosomal instability in malignant gliomas
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DOI：
10.1111/j.1349-7006.2009.01293.x
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发表时间：
2009-11-01
期刊：
影响因子：
5.7
通讯作者：
Sakaguchi, Nobuo
中科院分区：
文献类型：
--
作者：
Ohta, Kazutaka;Kuwahara, Kazuhiko;Sakaguchi, Nobuo
恶性胶质瘤（malignant glioma，MG）具有高度增殖性和侵袭性，其恶性特征与非整倍体和染色体不稳定性（chromosome instability，CIN）有关。在这里，我们发现，生发中心相关的核蛋白（GANP），酵母Sac 3的哺乳动物同源物的水平，显着降低MG与预后不良，因此，我们探讨了其减少对MG细胞系的细胞周期进程的影响。在101例成人MG中，通过实时逆转录-PCR检测，胶质母细胞瘤的ganp mRNA水平明显低于间变性星形细胞瘤。与ganpHigh组相比，ganpLow组MG表现出更多的恶性特征，10号染色体杂合性缺失，表皮生长因子受体基因扩增，预后明显差于ganpHigh组。通过RNA干扰（RNAi）方法耗尽ganp mRNA的人二倍体成纤维细胞显示S期细胞的百分比降低和细胞衰老表型。MG细胞系窝藏各种细胞周期检查点分子的异常显示有丝分裂检查点的滑移和超倍体细胞的比例增加后，ganp RNAi治疗。这些结果表明，GANP保护细胞免受DNA损伤引起的细胞衰老，并且GANP表达的显著降低通过产生超倍体和CIN导致恶性肿瘤。（Cancer Sci 2009）; 00：000-000）。
Malignant glioma (MG) is highly proliferative and invasive, with the malignant characteristics associated with aneuploidy and chromosomal instability (CIN). Here, we found that the level of germinal center-associated nuclear protein (GANP), a mammalian homologue of yeast Sac3, was markedly decreased in MGs with a poor prognosis; and thus we explored the effect of its decrease on cell-cycle progression of MG cell lines. Glioblastomas showed a significantly lower level of ganp mRNA than anaplastic astrocytomas, as measured by real-time reverse transcription-PCR, in 101 cases of adult MG. MGs of ganpLow expression displayed more malignant characteristics, with loss of heterozygosity on chromosome 10, epidermal growth factor receptor gene amplification, and significantly poorer prognosis than the ganpHigh group. Human diploid fibroblasts depleted of ganp mRNA by the RNA interference (RNAi) method showed a decreased percentage of S-phase cells and a cellular-senescence phenotype. MG cell lines harboring abnormalities of various cell-cycle checkpoint molecules displayed slippage of mitotic checkpoints and an increased proportion of hyperploid cells after ganp RNAi-treatment. These results suggest that GANP protects cells from cellular senescence caused by DNA damage and that a significant decrease in GANP expression leads to malignancy by generating hyperploidy and CIN. (Cancer Sci 2009); 00: 000-000).