Identification of CD133-positive radioresistant cells in atypical teratoid/rhabdoid tumor.
Identification of CD133-positive radioresistant cells in atypical teratoid/rhabdoid tumor.
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鉴定非典型畸胎组织/色肽肿瘤中CD133阳性辐射细胞。
DOI：
10.1371/journal.pone.0002090
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发表时间：
2008-05-07
期刊：
影响因子：
3.7
通讯作者：
Wong, Tai-Tong
中科院分区：
文献类型：
--
作者：
Chiou, Shih-Hwa;Kao, Chung-Lan;Chen, Yi-Wei;Chien, Chien-Shu;Hung, Shih-Chieh;Lo, Jeng-Fan;Chen, Yann-Jang;Ku, Hung-Hai;Hsu, Ming-Ta;Wong, Tai-Tong
非典型畸胎瘤/横纹肌样瘤（AT/RT）是中枢神经系统（CNS）的一种恶性肿瘤，好发于婴幼儿。最近的研究表明，CD 133可以被认为是脑癌干细胞（CSC）的标志物。然而，CD 133在AT/RT中的作用从未被研究过。在这里，我们报告的CD 133阳性细胞（CD 133+）的分离，发现有潜力分化成三个胚层组织，从9 AT/RT患者的组织。与CD 133-相比，CD 133+的迁移/侵袭/恶性和抗辐射能力显著增强。临床资料显示AT/RTs中CD 133+的数量与放射治疗抵抗的程度呈正相关。使用cDNA微阵列分析，用10戈伊电离辐射（IR）照射后0.5、2、6、12和24 h分析CD 133+和CD 133 −的基因毒性反应谱。然后我们验证了这些微阵列数据，并显示IR后p-ATM、p-RAD 17、和p-CHX 2，以及与CD 133-相比，CD 133+中BCL-2蛋白的表达增加。此外，我们发现CD 133+可以有效地抵抗顺铂和/或TRAIL诱导的凋亡的IR。免疫组织化学分析证实了在SCID小鼠中IR处理的CD 133+异种移植物中p-ATM和BCL-2蛋白的上调表达，但在IR处理的CD 133 −中没有。重要的是，BCL-2 siRNA与检查点激酶抑制剂脱溴海门醛地辛的组合可以显著改善CD 133+移植小鼠中IR的效果。总之，这是第一份表明CD 133 + AT/RT细胞表现出CSC特征的报告。CD 133+中的IR抗性和抗凋亡特性可能反映AT/RT的临床难治性恶性肿瘤，因此CD 133+中活化的p-ATM通路和BCL-2表达可能是改善未来致命疾病如AT/RT的治疗的可能靶点。
Atypical teratoid/rhabdoid tumor (AT/RT) is an extremely malignant neoplasm in the central nervous system (CNS) which occurs in infancy and childhood. Recent studies suggested that CD133 could be considered a marker for brain cancer stem-like cells (CSCs). However, the role of CD133 in AT/RT has never been investigated. Herein we report the isolation of CD133-positive cells (CD133+), found to have the potential to differentiate into three germ layer tissues, from tissues of nine AT/RT patients. The migration/invasion/malignancy and radioresistant capabilities of CD133+ were significantly augmented when compared to CD133−. The clinical data showed that the amount of CD133+ in AT/RTs correlated positively with the degree of resistance to radiation therapy. Using cDNA microarray analysis, the genotoxic–response profiles of CD133+ and CD133− irradiated with 10 Gy ionizing radiation (IR) were analyzed 0.5, 2, 6, 12 and 24 h post-IR. We then validated these microarray data and showed increased phosphorylation after IR of p-ATM, p-RAD17, and p-CHX2 as well as increased expression of BCL-2 protein in CD133+ compared to CD133−. Furthermore, we found that CD133+ can effectively resist IR with cisplatin- and/or TRAIL-induced apoptosis. Immunohistochemical analysis confirmed the up-regulated expression of p-ATM and BCL-2 proteins in IR-treated CD133+ xenotransgrafts in SCID mice but not in IR-treated CD133−. Importantly, the effect of IR in CD133+ transplanted mice can be significantly improved by a combination of BCL-2 siRNA with debromohymenialdisine, an inhibitor of checkpoint kinases. In sum, this is the first report indicating that CD133+ AT/RT cells demonstrate the characteristics of CSCs. The IR-resistant and anti-apoptotic properties in CD133+ may reflect the clinical refractory malignancy of AT/RTs and thus the activated p-ATM pathway and BCL-2 expression in CD133+ could be possible targets to improve future treatment of deadly diseases like AT/RT.
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影响因子：
7.3
作者：
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通讯作者：
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影响因子：
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Smith, M