The lung-enriched p53 mutants V157F and R158L/P regulate a gain of function transcriptome in lung cancer
The lung-enriched p53 mutants V157F and R158L/P regulate a gain of function transcriptome in lung cancer
复制标题
DOI：
10.1093/carcin/bgz087
复制
发表时间：
2020-01-01
期刊：
影响因子：
4.7
通讯作者：
McMahon, Steven B.
中科院分区：
文献类型：
--
作者：
Barta, Julie A.;Pauley, Kristen;McMahon, Steven B.
肺癌是美国癌症相关死亡的主要原因，肿瘤抑制基因TP 53的改变是所有肺癌组织学亚型中最常见的体细胞突变。TP 53的突变经常导致蛋白质不仅表现出肿瘤抑制能力的丧失，而且表现出致癌功能获得性（GOF）。例如，典型的p53热点突变体R175 H和R273 H在突变型p53的鼠模型中赋予肿瘤转移表型。据我们所知，很少研究的V157、R158和A159突变体的GOF表型--与其他实体瘤相比，它们在肺癌中发生的频率更高--尚未确定。在这项研究中，我们的目的是确定肺突变是否简单地等同于p53位点的完全丧失，或者它们是否额外获得了驱动新的下游效应通路的能力。使用公开的人类肺癌数据集，我们表征了具有V157、R158和A159 p53突变的患者。此外，我们在这里显示，突变型p53-V157 F，p53-R158 L和p53-R158 P的细胞系表现出典型的野生型p53靶基因的表达丧失。此外，这些肺富集的p53突变体调节先前不与p53功能相关的基因，包括PLAU。特别地，突变型p53抑制与增加的细胞活力、迁移和侵袭相关的基因。这些发现共同代表了肺富集的p53突变V157和R158调节人肺癌细胞中的新转录组并可能赋予从头功能的第一个证明。
Lung cancer is the leading cause of cancer-related deaths in the USA, and alterations in the tumor suppressor gene TP53 are the most frequent somatic mutation among all histologic subtypes of lung cancer. Mutations in TP53 frequently result in a protein that exhibits not only loss of tumor suppressor capability but also oncogenic gain-of-function (GOF). The canonical p53 hotspot mutants R175H and R273H, for example, confer upon tumors a metastatic phenotype in murine models of mutant p53. To the best of our knowledge, GOF phenotypes of the less often studied V157, R158 and A159 mutants-which occur with higher frequency in lung cancer compared with other solid tumors-have not been defined. In this study, we aimed to define whether the lung mutants are simply equivalent to full loss of the p53 locus, or whether they additionally acquire the ability to drive new downstream effector pathways. Using a publicly available human lung cancer dataset, we characterized patients with V157, R158 and A159 p53 mutations. In addition, we show here that cell lines with mutant p53-V157F, p53-R158L and p53-R158P exhibit a loss of expression of canonical wild-type p53 target genes. Furthermore, these lung-enriched p53 mutants regulate genes not previously linked to p53 function including PLAU. Paradoxically, mutant p53 represses genes associated with increased cell viability, migration and invasion. These findings collectively represent the first demonstration that lung-enriched p53 mutations at V157 and R158 regulate a novel transcriptome in human lung cancer cells and may confer de novo function.