TP53 gain-of-function mutation promotes inflammation in glioblastoma
TP53 gain-of-function mutation promotes inflammation in glioblastoma
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DOI：
10.1038/s41418-018-0126-3
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发表时间：
2019-02-01
影响因子：
12.4
通讯作者：
Kim, Hyunggee
中科院分区：
文献类型：
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作者：
Ham, Seok Won;Jeon, Hee-Young;Kim, Hyunggee
胶质母细胞瘤（GBM）是成人中最严重和最常见的脑肿瘤，其特征在于多个体细胞突变和异常激活的炎症反应。免疫细胞浸润和随后的炎症导致肿瘤生长和对治疗的抵抗。肿瘤抑制蛋白p53（TP 53）编码基因的体细胞功能缺失突变经常在各种癌症中观察到。然而，许多研究表明TP 53通过功能获得性（GOF）突变调节恶性表型。在这里，我们证明了TP 53 GOF突变促进GBM中的炎症。TP 53 GOF突变体的异位表达诱导转录组学变化，这导致与炎症和趋化性相关的基因签名的富集。生物信息学分析显示，由TP 53 GOF突变上调的基因签名与GBM的进展和较短的总生存期相关。我们还在GBM和其他癌症的临床数据库中观察到TP 53 GOF突变特征与炎症之间的显著相关性。TP 53 GOF突变体显示通过核因子κ B（NF kappa B）信号传导上调C-C基序趋化因子配体2（CCL 2）和肿瘤坏死因子α（TNFA）表达，从而增加小胶质细胞和单核细胞衍生的免疫细胞浸润。此外，TP 53 GOF突变和CCL 2和TNFA表达与GBM患者的肿瘤相关免疫呈正相关。总之，我们的研究结果表明，TP 53 GOF突变在炎症反应中起着至关重要的作用，从而恶化了GBM患者的预后结果。
Glioblastoma (GBM), the most severe and common brain tumor in adults, is characterized by multiple somatic mutations and aberrant activation of inflammatory responses. Immune cell infiltration and subsequent inflammation cause tumor growth and resistance to therapy. Somatic loss-of-function mutations in the gene encoding tumor suppressor protein p53 (TP53) are frequently observed in various cancers. However, numerous studies suggest that TP53 regulates malignant phenotypes by gain-of-function (GOF) mutations. Here we demonstrate that a TP53 GOF mutation promotes inflammation in GBM. Ectopic expression of a TP53 GOF mutant induced transcriptomic changes, which resulted in enrichment of gene signatures related to inflammation and chemotaxis. Bioinformatics analyses revealed that a gene signature, upregulated by the TP53 GOF mutation, is associated with progression and shorter overall survival in GBM. We also observed significant correlations between the TP53 GOF mutation signature and inflammation in the clinical database of GBM and other cancers. The TP53 GOF mutant showed upregulated C-C motif chemokine ligand 2 (CCL2) and tumor necrosis factor alpha (TNFA) expression via nuclear factor kappa B (NF kappa B) signaling, consequently increasing microglia and monocyte-derived immune cell infiltration. Additionally, TP53 GOF mutation and CCL2 and TNFA expression correlated positively with tumor-associated immunity in patients with GBM. Taken together, our findings suggest that the TP53 GOF mutation plays a crucial role in inflammatory responses, thereby deteriorating prognostic outcomes in patients with GBM.