Expression of p53 and p21 in primary glioblastomas
Expression of p53 and p21 in primary glioblastomas
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DOI：
10.1007/s00066-005-1304-z
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发表时间：
2005-03-01
影响因子：
3.1
通讯作者：
Schlegel, J
中科院分区：
文献类型：
--
作者：
Gross, MW;Kraus, A;Schlegel, J
背景和目的：原发性胶质母细胞瘤 (GBM) 具有高度放射抗性，与继发性 GBM 相比，它们具有野生型 (wt) p53 蛋白，该蛋白在这些肿瘤中的一部分是稳定的。因此，在体内研究了p53表达对于接受放化疗的患者是否具有预后价值。此外，作者试图根据 p53 和 p21 对电离辐射的反应，在体外鉴定对辐射具有不同敏感性的原发性 GBM 亚组。 材料和方法：对 31 名接受拓扑替康联合放化疗的原发性 GBM 患者的肿瘤组织样本进行了研究。通过免疫组织化学测定表达p53蛋白的细胞的百分比。此外，还建立并研究了 11 种原代 GBM 的原代培养物。在用 10 Gy 照射前以及照射后 2 小时和 8 小时评估 p53 和 p21 的表达。 Western分析法检测p53蛋白表达，逆转录聚合酶链式反应（RT-PCR）检测p21 mRNA表达。结果：31例患者肿瘤标本中p53阳性细胞的百分比范围为0％至28％，中值为4.3％。未发现与无病生存率或总生存率存在显着相关性。在体外，11 种原代 GBM 培养物中的 7 种检测到了 p53 蛋白。辐射后，7 个 p53 阳性培养物中有 6 个发现 p53 蛋白表达下降。没有基础 p53 表达的一半培养物（四个中的两个）在辐射后显示 p53 表达增加。在 11 种培养物中的 6 种中检测到 p21 的基础过度表达；六分之四的辐射导致 p21 表达下降。在最初显示缺乏 p21 表达的所有细胞系（十一个中的五个）中，辐射诱导了 p21 表达。尽管有这些反应，但在任何 GBM 培养物中均未检测到 G1 期停滞。结论：体内 p53 蛋白表达与原发性 GBM 患者的预后无关。因此，p53 蛋白含量本身似乎并不是原发性 GBM 预后适应治疗的有用预后因素。相比之下，体外原代 GBM 细胞的 p53 和 p21 途径对电离辐射表现出不同且独立的反应。 G1 停滞的失败似乎是由于 p53 通路的功能缺陷所致，要么是因为 p21 没有被诱导，要么是因为 p21 下游存在未识别的缺陷。
Background and Purpose: Primary ghoblastomas (GBMs) are highly radioresistant, and in contrast to secondary GBMs, they bear wild-type (wt) p53 protein, which is stabilized in a proportion of these tumors. Therefore, it was investigated in vivo whether p53 expression has prognostic value in patients undergoing radiochemotherapy. Additionally, the authors tried to identify, in vitro, subgroups of primary GBM with different susceptibilities to irradiation, on the basis of their p53 and p21 responses to ionizing radiation.Material and Methods: Tumor tissue samples from 31 patients suffering from primary GBM undergoing a combined radiochemotherapy with topotecan were investigated. The percentage of cells expressing p53 protein was determined immunohistochemically. Additionally, primary cultures from eleven primary GBMs were established and investigated. p53 and p21 expressions were evaluated before irradiation with 10 Gy and at 2 and 8 h after irradiation. p53 protein expression was measured by Western analysis and p21 mRNA expression by reverse transcription-polymerase chain reaction (RT-PCR).Results: The percentage of p53-positive cells within the tumor specimens obtained from the 31 patients ranged from 0% to 28%, the median value being 4.3%. No significant correlation with disease-free survival or overall survival was found. In vitro, p53 protein was detected in seven of eleven cultures from primary GBM. After irradiation a decrease in p53 protein expression was seen in six of the seven p53-positive cultures. Half of the cultures (two of four) without basal p53 expression showed an increase in p53 expression after irradiation. Basal overexpression of p21 was detected in six of the eleven cultures; in four out of six irradiation led to a decrease in p21 expression. In all cell Lines (five of eleven) initially showing absent p21 expression, irradiation induced p21 expression. Despite these responses, G1 arrest was not detectable in any of the GBM cultures.Conclusion: p53 protein expression in vivo does not correlate with the outcome of patients with primary GBM. Therefore, p53 protein content per se does not appear to be a helpful prognostic factor for prognosis-adapted therapy in primary GBM. By contrast, primary GBM cells in vitro show different and independent responses in their p53 and p21 pathways to ionizing radiation. The failure of G1 arrest seems to be due to a functional defect in the p53 pathway, either because p21 was not induced or because of an unidentified defect downstream from p21.