p53 pathway dysfunction in primary childhood ependymomas
p53 pathway dysfunction in primary childhood ependymomas
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DOI：
10.1002/pbc.20532
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发表时间：
2006-05-01
影响因子：
3.2
通讯作者：
Vassal, G
中科院分区：
文献类型：
--
作者：
Gaspar, N;Grill, J;Vassal, G
背景儿童室管膜瘤仍然是一个主要的治疗挑战，尽管手术，化疗和放疗。我们假设p53功能可能在室管膜瘤中被废除，并与其对抗癌治疗的抵抗有关。Procedure.对24例诊断或复发的原发性室管膜瘤进行p53通路分析，分别使用酵母功能测定、RT-PCR、Western印迹分析和/或免疫组化检测TP 53突变、p14（ARF）缺失和启动子高甲基化、MDM 2和PAX 5表达。在两个室管膜瘤异种移植模型IGREP 37和IGREP 83中，使用Western印迹和流式细胞术分析评价了p53介导的对辐射诱导的DNA损伤的反应，IGREP 37和IGREP 83来源于原发性间变性儿童室管膜瘤。结果在原发性室管膜瘤和移植瘤中未检测到TP 53、MDM 2、p1（4ARF）、PAX 5基因异常。有趣的是，尽管没有这些异常，p53诱导的p21介导的G（1）生长停滞在IGREP 37异种移植肿瘤中对辐射的反应发生了改变。虽然辐射诱导坏死和凋亡细胞死亡，IGREP 37肿瘤是中度敏感的放射治疗在体内。相比之下，照射在p53功能性IGREP 83异种移植物中产生显著的肿瘤生长延迟和肿瘤消退。结论室管膜瘤中p53介导的生长停滞的改变可能与这些肿瘤的放射抗性有关，需要进一步评估。
Background. Childhood ependymoma remains a major therapeutic challenge despite Surgery, chemotherapy, and irradiation. We hypothesized that p53 function might be abrogated in ependymomas and implicated in their resistance to anti-cancer therapy. Procedure. Primary ependymomas at diagnosis or relapse from 24 children were analyzed for p53 pathway, using a functional assay in yeast, RT-PCR, Western blot analysis, and/or immunohistochemistry for TP53 mutation, p14(ARF) deletion and promoter hypermethylation, MDM2 and PAX5 expression, respectively. p53-mediated response to radiation-induced DNA damage was evaluated using Western blot and flow cytometry analysis in two ependymoma xenograft models, IGREP37 and IGREP83, derived from primary anaplastic childhood ependymomas. Results. No TP53, MDM2, p1(4ARF), PAX5 gene abnormalities were detected in the primary ependymomas tumors and xenografts tested. Interestingly, despite the lack of these abnormalities, p53 induced p21-mediated G(1) growth arrest in response to irradiation was altered in the IGREP37 xenograft tumors. Although irradiation induced necrosis and apoptotic cell death, IGREP37 tumors were moderately sensitive to radiation therapy in vivo. In contrast, irradiation yielded significant tumor growth delays and tumor regressions in the p53 functional IGREP83 xenografts. Conclusion. Alterations in p53-mediated growth arrest in ependymomas might be implicated in the radio-resistance of these tumors and demand further evaluation.