Gene Amplifications in Well-Differentiated Pancreatic Neuroendocrine Tumors Inactivate the p53 Pathway.
Gene Amplifications in Well-Differentiated Pancreatic Neuroendocrine Tumors Inactivate the p53 Pathway.
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DOI：
10.1177/1947601910371979
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发表时间：
2010-05-15
期刊：
影响因子：
--
通讯作者：
Tang LH
中科院分区：
文献类型：
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作者：
Hu W;Feng Z;Modica I;Klimstra DS;Song L;Allen PJ;Brennan MF;Levine AJ;Tang LH
神经内分泌肿瘤（NET）包括一组源自弥漫性神经内分泌系统或胰腺胰岛内分泌细胞的罕见肿瘤。 NET 的分子机制在很大程度上尚不清楚。抑癌基因p53在维持基因组稳定性和肿瘤预防方面发挥着关键作用。 p53 通路受到许多蛋白质的严格调控，其中 MDM2、MDM4 和 WIP1 是 p53 蛋白质水平或活性的关键负调节因子。这些负调节因子的异常激活会削弱 p53 功能，而 p53 功能是肿瘤发生的重要机制。在这项研究中，研究了胰腺 NET 的几种遗传改变。通过基于阵列的比较基因组杂交检查，这些肿瘤在整个基因组中表现出各种染色体畸变。尽管 p53 突变在 NET 中很少见（<3%），但本研究提供的证据表明，胰腺 NET 中的 p53 通路通过其负调节因子的异常激活而发生改变。大部分胰腺 NET 含有 MDM2 (22%)、MDM4 (30%) 和 WIP1 (51%) 的额外基因拷贝，这些拷贝与相应 mRNA 和蛋白质的表达相关。此外，MDM2 SNP309 的 G/G 基因型的频率较高（对照群体中为 23% vs. 15%），MDM2 基因中的功能性单核苷酸多态性会减弱 p53 蛋白的功能。总体而言，大约 70% 的胰腺 NET 具有其中一种或多种基因变化。这些发现表明，p53 功能的负调节可能是胰腺 NET 启动和/或进展的重要机制，p53 的重新激活可能是该疾病患者的潜在治疗策略。
Neuroendocrine tumors (NETs) comprise a group of rare tumors derived from the diffuse neuroendocrine system or islet endocrine cells of the pancreas. The molecular mechanisms underlying NETs are largely unknown. The tumor suppressor p53 plays a critical role in maintaining genomic stability and tumor prevention. The p53 pathway is tightly regulated by a number of proteins, among which MDM2, MDM4, and WIP1 are key negative regulators of p53 protein levels or activity. Aberrant activation of these negative regulators can attenuate the p53 function that serves as an important mechanism of tumorigenesis. In this study, several genetic alterations in pancreatic NETs were studied. These tumors exhibit various chromosomal aberrations throughout the whole genome as examined by array-based comparative genomic hybridization. Although p53 mutations are rare in NETs (<3%), this study presents evidence that the p53 pathway is altered in pancreatic NETs through aberrant activation of its negative regulators. A high percentage of pancreatic NETs contain extra gene copies of MDM2 (22%), MDM4 (30%), and WIP1 (51%), which are correlated with expression of corresponding mRNAs and proteins. In addition, there is a higher frequency (23% v. 15% in the control population) of the G/G genotype of MDM2 SNP309, a functional single-nucleotide polymorphism in the MDM2 gene that attenuates the function of the p53 protein. Overall, approximately 70% of pancreatic NETs have one or more of these genetic changes. These findings suggest that the negative regulation of p53 function could be an important mechanism for the initiation and/or progression of pancreatic NETs, and reactivation of p53 could be a potential therapeutic strategy for patients with this disease.