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在人类甲状腺有机体模型中,在发生DNA损伤时,具有生殖系PTEN突变的不同PTEN-p53相互作用

Juan Andres Venegas, Omer Enes Onur, Shin Chung Kang

Endocrine-related cancer

|February 19, 2025

概括

生殖系PTEN变体影响DNA损伤对辐射的反应. 特定的PTEN突变,如M134R,损害p53激活,在PTEN hamartoma瘤综合征 (PHTS) 患者中增加差异化甲状腺癌 (DTC) 风险.

科学领域:

遗传学和基因组学在
在瘤学瘤学.
分子生物学分子生物学

背景情况:

在PTEN基因的生殖基因突变导致PTEN hamartoma瘤综合征 (PHTS),显著增加差异化甲状腺癌 (DTC) 的风险.
导致DTC发生的特定PTEN变异在很大程度上是未知的,尽管PTEN在对抗PI3K-AKT通路的作用在零星DTC中至关重要.
电离辐射是可能导致瘤发生的环境因素,其与生殖线PTEN变体在DNA损伤反应中的相互作用尚未探索.

研究的目的:

为了研究电离辐射如何改变DNA损伤反应,基于不同的生殖线PTEN变体.
为了确定与DTC相关的特定PTEN变异是否会在辐射诱导的DNA损伤后产生亲瘤分子特征.
阐明在具有明显PTEN突变的PHTS患者中DTC的差异性风险背后的分子机制.

主要方法:

引入了与DTC相关的 (PTEN M134R) 和与DTC无关的 (PTEN G132D) 生殖系PTEN突变基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因基因.
从野生类型和异性PTEN突变hiPSC产生的功能性甲状腺器官.
通过大量和单细胞RNA测序分析了这些器官中的辐射诱导的转录组变化.

主要成果:

与PTEN WT/G132D的甲状腺器官相比,PTEN WT/M134R的甲状腺器官在辐射后对p53网络的上调作用较小.
这种差异性p53激活可能由AKT依赖的MDM2失活和直接的PTEN-p53相互作用介导.
这种PTEN M134R变种似乎通过受损的PTEN-p53网络相互作用来阻碍p53通路的激活.

结论:

PTEN M134R变体与减少的DNA损伤反应有关,特别是减少了p53通路激活,这解释了其与PHTS中DTC敏感性增加的联系.
了解这些对DNA损伤的变异特异性反应对于PHTS患者的风险分层和潜在的治疗策略至关重要.
作为基因组的守护者,PTEN的作用进一步突出,因为它与p53网络的相互作用,以应对电离辐射等环境压力因素.

关键词:

造成的DNA损伤是DNA损伤.在这里,我们可以使用PTEN.瘤发生的发生因子.在 p53 里,p53 是一个 p53 的类型.甲状腺有机物质甲状腺有机物质

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