当前位置: X-MOL 学术Mol. Cancer Res. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
MicroRNA-324-5p-CUEDC2 Axis Mediates Gain-of-Function Mutant p53-Driven Cancer Stemness
Molecular Cancer Research ( IF 5.2 ) Pub Date : 2021-10-01 , DOI: 10.1158/1541-7786.mcr-20-0717
Dishari Ghatak 1 , Arindam Datta 1 , Tanaya Roychowdhury 1 , Samit Chattopadhyay 1, 2 , Susanta Roychoudhury 1, 3
Affiliation  

Regulation of cancer stemness has recently emerged as a new gain-of-function (GOF) property of mutant p53. In this study, we identify miR-324-5p as a critical epigenetic regulator of cancer stemness and demonstrate its role in mediating GOF-mutant p53-driven stemness phenotypes. We report that miR-324–5p is upregulated in human cancer cell lines and non–small cell lung carcinoma (NSCLC) tumors carrying TP53 GOF mutations. Mechanistically, we show that GOF mutant p53 upregulates miR-324–5p expression via c-Myc, an oncogenic transcription factor in cancer cells. Our experimental results suggest that miR-324–5p–induced CSC phenotypes stem from the downregulation of CUEDC2, a downstream target gene of miR-324–5p. Accordingly, CUEDC2 complementation diminishes elevated CSC marker expression in miR-324–5p–overexpressing cancer cells. We further demonstrate that mutant p53 cancer cells maintain a low level of CUEDC2 that is rescued upon miR-324–5p inhibition. Importantly, we identify CUEDC2 downregulation as a novel characteristic feature of TP53 -mutated human cancers. We show that activation of NF-κB due to downregulation of CUEDC2 by miR-324–5p imparts stemness in GOF mutant p53 cancer cells. Finally, we provide evidence that TP53 mutations coupled with high miR-324–5p expression predict poor prognosis in patients with lung adenocarcinoma. Thus, our study delineates an altered miR-324–5p-CUEDC2-NF-κB pathway as a novel regulator of GOF mutant p53-driven cancer stemness. Implications: Our findings implicate miRNA-324–5p as a novel epigenetic modifier of human cancer stemness. This article is featured in Highlights of This Issue, [p. 1611][1] [1]: /lookup/volpage/19/1611?iss=10

中文翻译:

MicroRNA-324-5p-CUEDC2 轴介导功能获得突变体 p53 驱动的癌症干性

癌症干性的调节最近已成为突变 p53 的一种新的功能获得 (GOF) 特性。在这项研究中,我们将 miR-324-5p 鉴定为癌症干性的关键表观遗传调节因子,并证明其在介导 GOF 突变 p53 驱动的干性表型中的作用。我们报道 miR-324-5p 在人类癌细胞系和携带 TP53 GOF 突变的非小细胞肺癌 (NSCLC) 肿瘤中上调。从机制上讲,我们发现 GOF 突变体 p53 通过 c-Myc 上调 miR-324-5p 的表达,c-Myc 是癌细胞中的一种致癌转录因子。我们的实验结果表明,miR-324-5p 诱导的 CSC 表型源于 CUEDC2 的下调,CUEDC2 是 miR-324-5p 的下游靶基因。因此,CUEDC2 互补降低了过表达 miR-324-5p 的癌细胞中升高的 CSC 标志物表达。我们进一步证明突变的 p53 癌细胞维持低水平的 CUEDC2,在 miR-324-5p 抑制后得以挽救。重要的是,我们将 CUEDC2 下调确定为 TP53 突变的人类癌症的新特征。我们表明,由于 miR-324-5p 下调 CUEDC2 导致的 NF-κB 激活赋予了 GOF 突变 p53 癌细胞的干性。最后,我们提供的证据表明 TP53 突变与高 miR-324-5p 表达相结合可预测肺腺癌患者的不良预后。因此,我们的研究描述了一个改变的 miR-324-5p-CUEDC2-NF-κB 通路作为 GOF 突变 p53 驱动的癌症干性的新调节剂。启示:我们的研究结果表明 miRNA-324-5p 是人类癌症干性的一种新的表观遗传修饰物。这篇文章被收录在本期的亮点中,[p. 1611][1][1]:
更新日期:2021-10-04
down
wechat
bug