Transcription factor E2F-1 acts as a growth-promoting factor and is associated with adverse prognosis in non-small cell lung carcinomas
Transcription factor E2F-1 acts as a growth-promoting factor and is associated with adverse prognosis in non-small cell lung carcinomas
复制标题
DOI：
10.1002/path.1121
复制
发表时间：
2002-10-01
影响因子：
7.3
通讯作者：
Papavassiliou, AG
中科院分区：
文献类型：
--
作者：
Gorgoulis, VG;Zacharatos, P;Papavassiliou, AG
许多上游刺激性和抑制性信号会融合到控制细胞周期进展的PRB/E2F途径，但有关E2F-1在原发性恶性肿瘤中的改变的信息非常有限。几项体外研究报告说，E2F-1可以用作癌蛋白或肿瘤抑制蛋白。鉴于该二分法的功能及其在细胞周期控制中的关键作用，这项研究检查了在87个非小细胞肺癌（NSCLCS）小组中E2F-1的以下四个方面，此前对PRB中的缺陷进行了分析-p53-MDM2网络：首先，E2F-1在蛋白质，mRNA和DNA水平上的状态；其次，它与肿瘤的动力学参数和基因组不稳定性的关系；第三，它与其转录共激活因子CBP，下游靶PCNA和主细胞周期调节的状态以及E2F-1相互作用分子PRB，p53和MDM2的联系；第四，它对临床结果的影响。在肿瘤区域，E2F-1及其共激活因子CBP的蛋白质水平明显高于相应的正常上皮（P <0.001）。在检查的82％的病例中，E2F-1过表达与E2F-1 mRNA水平升高有关。后者的发现，以及观察到的E2F-1基因扩增的低频（9％），表明NSCLC中E2F-1蛋白过表达的主要机制在转录水平上是放松管制的。突变分析显示，只有一个样品在密码子371（glu-> asp）上具有体细胞突变，一个样品在密码子393（gly-> ser）处携带多态性。 E2F-1阳性增加的癌表明其生长指数显着增加（r = 0.402，p = 0.001），并且与不良预后有关（Cox回归分析通过P = 0.033）。与生长正相关的主要决定因素是E2F-1染色和增殖之间的平行增加（r = 0.746，p <0.001），而细胞凋亡不受E2F-1状态的影响。此外，与PRB-P53-MDM2网络状态的相关性表明，异常PRB表达的病例显示出更高的E2F-1指数（p = 0.033），而在癌症组中发现了类似的关联，并且对癌症进行了降低调节。 P53-MDM2反馈回路。总之，结果表明，E2F-1过表达可能通过促进增殖而导致NSCLC的发展，并提供证据表明，在遗传背景中，使用PRB-P53-MDM2电路的遗传背景进一步增强了这种作用。版权（C）2002 John Wiley＆Sons，Ltd。
Numerous upstream stimulatory and inhibitory signals converge to the pRb/E2F pathway, which governs cell-cycle progression, but the information concerning alterations of E2F-1 in primary malignancies is very limited. Several in vitro studies report that E2F-1 can act either as an oncoprotein or as a tumour suppressor protein. In view of this dichotomy in its functions and its critical role in cell cycle control, this study examined the following four aspects of E2F-1 in a panel of 87 non-small cell lung carcinomas (NSCLCs), previously analysed for defects in the pRb-p53-MDM2 network: firstly, the status of E2F-1 at the protein, mRNA and DNA levels; secondly, its relationship with the kinetic parameters and genomic instability of the tumours; thirdly, its association with the status of its transcriptional co-activator CBP, downstream target PCNA and main cell cycle regulatory and E2F-1-interacting molecules pRb, p53 and MDM2; and fourthly, its impact on clinical outcome. The protein levels of E2F-1 and its co-activator CBP were significantly higher in the tumour area than in the corresponding normal epithelium (p < 0.001). E2F-1 overexpression was associated with increased E2F-1 mRNA levels in 82% of the cases examined. The latter finding, along with the low frequency of E2F-1 gene amplification observed (9%), suggests that the main mechanism of E2F-1 protein overexpression in NSCLCs is deregulation at the transcriptional level. Mutational analysis revealed only one sample with a somatic mutation at codon 371 (Glu --> Asp) and one carrying a polymorphism at codon 393 (Gly --> Ser). Carcinomas with increased E2F-1 positivity demonstrated a significant increase in their growth indexes (r = 0.402, p = 0.001) and were associated with adverse prognosis (P = 0.033 by Cox regression analysis). The main determinant of the positive association with growth was the parallel increase between E2F-1 staining and proliferation (r = 0.746, p < 0.001), whereas apoptosis was not influenced by the status of E2F-1. Moreover, correlation with the status of the pRb-p53-MDM2 network showed that the cases with aberrant pRb expression displayed significantly higher E2F-1 indexes (p = 0.033), while a similar association was noticed in the group of carcinomas with deregulation of the p53-MDM2 feedback loop. In conclusion, the results suggest that E2F-1 overexpression may contribute to the development of NSCLCs by promoting proliferation and provide evidence that this role is further enhanced in a genetic background with deregulated pRb-p53-MDM2 circuitry. Copyright (C) 2002 John Wiley & Sons, Ltd.