MDM2-p53 Interactions in Human Hepatocellular Carcinoma: What Is the Role of Nutlins and New Therapeutic Options?
MDM2-p53 Interactions in Human Hepatocellular Carcinoma: What Is the Role of Nutlins and New Therapeutic Options?
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DOI：
10.3390/jcm7040064
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发表时间：
2018-03-27
影响因子：
3.9
通讯作者：
Azer SA
中科院分区：
文献类型：
--
作者：
Azer SA
人肝细胞癌（HCC）是世界范围内第五大常见癌症，并且与不良预后相关。HCC发病机制的分子机制一直是一个持续关注的领域，最近使用下一代测序（NGS）的研究揭示了许多以前未解决的问题。使用HCC样本的分子研究主要是为了确定导致HCC的基本机制并确定更有效的治疗方法。响应于细胞应激（例如，DNA损伤或癌基因），激活的p53激发适当的反应，目的是DNA修复，遗传稳定性，细胞周期停滞，和DNA损伤细胞的删除。另一方面，鼠双微体2（MDM 2）癌基因蛋白是p53的重要细胞拮抗剂。MDM 2通过诱导p53蛋白降解来负调节p53活性。然而，目前的研究表明，MDM 2-p53相互作用的机制比以前认为的更复杂。微阵列数据为HCC中的转录变化提供了新的见解。最近，Nutlin-3显示出对抗p53-MDM 2结合的效力和p53稳定性的增强以及具有潜在治疗效果的p53细胞积累的增加。本文就p53-MDM 2通路的分子机制、影响p53-MDM 2通路的生物学因素及其在肝癌发病中的作用作一综述。它还讨论了Nutlin-3治疗在诱导HCC生长停滞中的作用，并阐述了该领域未来的研究方向。对p53-MDM 2相互作用的生物学的更多研究可能会更好地理解这些机制，并发现新的生物标志物，敏感的预后指标以及新的HCC治疗干预措施。
Human hepatocellular carcinoma (HCC) is the fifth most common cancer and is associated with poor prognosis worldwide. The molecular mechanisms underlying the pathogenesis of HCC have been an area of continuing interest, and recent studies using next generation sequencing (NGS) have revealed much regarding previously unsettled issues. Molecular studies using HCC samples have been mainly targeted with the aim to identify the fundamental mechanisms contributing to HCC and identify more effective treatments. In response to cellular stresses (e.g., DNA damage or oncogenes), activated p53 elicits appropriate responses that aim at DNA repair, genetic stability, cell cycle arrest, and the deletion of DNA-damaged cells. On the other hand, the murine double minute 2 (MDM2) oncogene protein is an important cellular antagonist of p53. MDM2 negatively regulates p53 activity through the induction of p53 protein degradation. However, current research has shown that the mechanisms underlying MDM2-p53 interactions are more complex than previously thought. Microarray data have added new insight into the transcription changes in HCC. Recently, Nutlin-3 has shown potency against p53-MDM2 binding and the enhancement of p53 stabilization as well as an increment of p53 cellular accumulation with potential therapeutic effects. This review outlines the molecular mechanisms involved in the p53-MDM2 pathways, the biological factors influencing these pathways, and their roles in the pathogenesis of HCC. It also discusses the action of Nutlin-3 treatment in inducing growth arrest in HCC and elaborates on future directions in research in this area. More research on the biology of p53-MDM2 interactions may offer a better understanding of these mechanisms and discover new biomarkers, sensitive prognostic indicators as well as new therapeutic interventions in HCC.
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DOI：
10.1073/pnas.76.5.2420
发表时间：
1979-01-01
影响因子：
11.1
作者：
DELEO, AB;JAY, G;OLD, LJ
通讯作者：
OLD, LJ
影响因子：
64.5
作者：
ELDEIRY, WS;TOKINO, T;VOGELSTEIN, B
通讯作者：
VOGELSTEIN, B
影响因子：
56.9
作者：
AGUILAR, F;HARRIS, CC;CERUTTI, P
通讯作者：
CERUTTI, P
影响因子：
64.8
作者：
BRESSAC, B;KEW, M;OZTURK, M
通讯作者：
OZTURK, M
影响因子：
64.5
作者：
Bond, GL;Hu, WW;Levine, AJ
通讯作者：
Levine, AJ