p53 apoptotic pathway molecules are frequently and simultaneously altered in nonsmall cell lung carcinoma
p53 apoptotic pathway molecules are frequently and simultaneously altered in nonsmall cell lung carcinoma
复制标题
DOI：
10.1002/cncr.20164
复制
发表时间：
2004-04-15
期刊：
影响因子：
6.2
通讯作者：
Sekido, Y
中科院分区：
文献类型：
--
作者：
Mori, S;Ito, G;Sekido, Y
背景肺癌显示p53肿瘤抑制因子的频繁失活，其调节细胞凋亡途径。本研究的目的是评估p53凋亡通路在非小细胞肺癌（NSCLC）中的改变，特别是在p53无改变的肿瘤中。在118例NSCLC标本中研究了p53、其上游调节因子（p14（ARF）和HDM 2）以及凋亡途径的下游效应因子（BAX和BCL 2）。通过单链构象多态性分析（涵盖外显子2-11）和免疫组织化学（IHC）分析p53。用甲基化特异性聚合酶链反应和免疫组化方法分析p14（ARF）。使用Southern印迹分析和IHC分析HDM 2。通过IHC分析BAX和BCL 2。还研究了调节HDM 2稳定性的另外两种上游调节剂，PTEN和HAUSP。在分析的118例NSCLC标本中，74例（63%）肿瘤中检测到p53改变，53例（45%）肿瘤中检测到p14（ARF）失活，31例（26%）肿瘤中发现HDM 2过表达，包括6例基因扩增肿瘤。虽然同时检测到p53失活和HDM 2过表达，但仅在无p53突变的肿瘤标本中观察到HDM 2基因扩增。IHC显示88例肿瘤中有22例（25%）PTEN表达下调。HAUSP北方印迹分析表明，基因表达的几倍的差异，不相关的p53的变化。在118例NSCLC标本中，BAX和BCL 2表达分别在46例（39%）和17例（14%）中检出。北方印迹分析未发现参与p53转录调控的ASPP 1和ASPP 2的异常表达。总体而言，发现两种或多种p53通路组分在NSCLC患者中频繁改变。超过90%的改变是由于p53，p14（ARF）或HDM 2的异常。因此，p53通路的一种或多种组分的失活似乎是大多数NSCLC发展的先决条件。(C)2004年美国癌症协会。
BACKGROUND. Lung carcinomas show frequent inactivation of the p53 tumor suppressor, which regulates an apoptotic pathway. The objective of the current study was to assess how the p53 apoptotic pathway is altered in nonsmall cell lung carcinoma (NSCLC), especially in tumors without p53 alterations.METHODS. p53, its upstream regulators (p14(ARF) and HDM2), and downstream effectors of the apoptotic pathway (BAX and BCL2) were studied in 118 NSCLC specimens. p53 was analyzed by single-stranded conformation polymorphism analysis covering exons 2-11 and by immunohistochemistry (IHC). p14(ARF) was analyzed by methylation-specific polymerase chain reaction and IHC. HDM2 was analyzed using Southern blot analysis and IHC. BAX and BCL2 were analyzed by IHC. Two other upstream regulators that regulate the stability of HDM2, PTEN and HAUSP, also were studied.RESULTS. Of 118 NSCLC specimens that were analyzed, p53 alterations were detected in 74 tumors (63%), p14(ARF) inactivation was detected in 53 tumors (45%), and overexpression of HDM2 was found in 31 tumors (26%), including 6 tumors with gene amplification. Although p53 inactivation and HDM2 overexpression were detected simultaneously, HDM2 gene amplification was observed only in tumor specimens without p53 mutations. IHC revealed PTEN down-regulation in 22 of 88 tumors (25%). HAUSP Northern blot analysis demonstrated several-fold differences in gene expression that did not correlate with p53 alterations. Of 118 NSCLC specimens, expression of BAX and BCL2 expression were detected in 46 tumors (39%) and 17 tumors (14%), respectively. Finally, ASPP1 and ASPP2, molecules invovled in mediating the transcription function of p53, were not found to be aberrantly expressed when tested by Northern blot analysis.CONCLUSIONS. overall, two or more p53 pathway components were found to be frequently altered in patients with NSCLC. Greater than 90% of the alterations were due to abnormalities of p53, p14(ARF), or HDM2. Therefore, the inactivation of one or more components of the p53 pathway appears to be a prerequisite for the development of most NSCLCs. (C) 2004 American Cancer Society.