ORAOV1, CCND1, and MIR548K Are the Driver Oncogenes of the 11q13 Amplicon in Squamous Cell Carcinoma.
ORAOV1, CCND1, and MIR548K Are the Driver Oncogenes of the 11q13 Amplicon in Squamous Cell Carcinoma.
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DOI：
10.1158/1541-7786.mcr-23-0746
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发表时间：
2024-02-01
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影响因子：
--
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11q13扩增是人类癌症中的常见事件，特别是在鳞状细胞癌（SCC）中。尽管几乎总是跨越10个基因，但尚不清楚扩增子的哪些遗传组分是SCC中的关键驱动事件。利用通过Cas9-RNP电穿孔进行的有效的原代人角质形成细胞基因组编辑的计算、体外、离体和体内模型的组合鉴定了0RA0V1、CCND1和MIR548K作为头颈部SCC中扩增子的关键驱动因子。CCND1扩增以CDK4/6/RB1非依赖性方式驱动细胞周期，并可能赋予对RRM2的新依赖性。MIR548K有助于上皮-间充质转化。最后，我们确定了ORAOV 1作为一种癌基因，可能通过其调节活性氧的能力发挥作用。因此，11q13扩增子通过至少三个独立的遗传元件驱动SCC，并为这种病态和致命的疾病提供了治疗靶点。这项工作展示了新的机制和方法，以针对鳞状细胞癌中最常见的扩增机制，鳞状细胞癌是人类癌症中最普遍和最致命的形式之一。
11q13 amplification is a frequent event in human cancer and in particular in squamous cell carcinomas (SCC). Despite almost invariably spanning 10 genes, it is unclear which genetic components of the amplicon are the key driver events in SCC. A combination of computational, in vitro, ex vivo, and in vivo models leveraging efficient primary human keratinocyte genome editing by Cas9-RNP electroporation, identified ORAOV1, CCND1, and MIR548K as the critical drivers of the amplicon in head and neck SCC. CCND1 amplification drives the cell cycle in a CDK4/6/RB1-independent fashion and may confer a novel dependency on RRM2. MIR548K contributes to epithelial–mesenchymal transition. Finally, we identify ORAOV1 as an oncogene that acts likely via its ability to modulate reactive oxygen species. Thus, the 11q13 amplicon drives SCC through at least three independent genetic elements and suggests therapeutic targets for this morbid and lethal disease. This work demonstrates novel mechanisms and ways to target these mechanisms underlying the most common amplification in squamous cell carcinoma, one of the most prevalent and deadly forms of human cancer.
影响因子：
37.3
作者：
Zhang W;Hong R;Li L;Wang Y;Du P;Ou Y;Zhao Z;Liu X;Xiao W;Dong D;Wu Q;Chen J;Song Y;Zhan Q
通讯作者：
Zhan Q
影响因子：
5.6
作者：
Du JJ;Zhan CY;Lu Y;Cui HR;Wang XY
通讯作者：
Wang XY