功能性 RNAi 筛选确定 G2/M 和着丝点成分是头颈部鳞状细胞癌中 TNFα/NF-κB 促生存信号的调节因子。

IF 2 Q3 ONCOLOGY

Cancer research communications Pub Date : 2024-11-01 DOI:10.1158/2767-9764.CRC-24-0274

Ethan L Morgan, Anthony D Saleh, Shaleeka Cornelius, Sophie G Carlson, Tiffany Toni, Hui Cheng, Jun Jeon, Ramya Viswanathan, Xinping Yang, Christopher Silvin, Paul E Clavijo, Anastasia L Sowers, James B Mitchell, Pinar Ormanoglu, Madhu Lal Nag, Scott E Martin, Zhong Chen, Carter Van Waes

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引用次数: 0

摘要

在包括头颈部鳞状细胞癌（HNSCC）在内的多种癌症中，转录因子 NF-κB 促进了癌细胞对肿瘤坏死因子-α（TNFα）介导的细胞毒性的免疫和辐射抗性。癌症基因组图谱（The Cancer Genome Atlas，TCGA）发现，约40%的HNSCC存在TNFα/NF-κB信号轴的基因组改变。然而，鉴定导致TNFα/NF-κB异常激活和耐药性的治疗靶点一直是个挑战。在这里，我们利用平行的 NF-κB β-内酰胺酶报告和细胞活力测定法，在一种 HNSCC 细胞系中进行了功能性 RNAi 筛选，以确定 TNFα 诱导的 NF-κB 激活和细胞活力的调节因子。除了典型 TNFα/NF-κB 信号转导的多种成分外，我们还发现了 WNT、NOTCH 和 TGFβ 通路的成分，我们以前曾证实这些成分有助于 NF-κB 的非典型激活。意想不到的是，我们还观察到多种 G2/M 细胞周期激酶（AURKA、PLK1、WEE1、TTK）和结构性动点核/微管成分（NDC80、NUF2）调节 TNFα 诱导的 NF-κB 激活和细胞活力。其中几个靶点抑制了 TNF 诱导的 RELA 核转位，这与之前将 NF-B 激活与 G2/M 激酶或微管组装联系起来的报道一致。对未被充分研究的有丝分裂激酶TTK/MPS1的进一步研究表明，抑制或耗竭TTK/MPS1可减少TNFα诱导的RELA核转位，促进细胞死亡、DNA损伤、多倍体和有丝分裂灾难，从而导致放射致敏。总之，我们的RNAi筛选确定了G2/M细胞周期检查点/着丝点元件与NF-κB活性之间的关键联系，以及可使HNSCC细胞对TNFα或辐射敏感的靶点。

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Functional RNAi Screening Identifies G2/M and Kinetochore Components as Modulators of TNFα/NF-κB Prosurvival Signaling in Head and Neck Squamous Cell Carcinoma.

Significance: Here, RNAi library screening reveals that multiple G2/M and kinetochore components, including TTK/monopolar spindle 1, modulate TNFα-induced NF-κB activation, cell survival, and genotoxicity, underscoring their potential importance as therapeutic targets in HNSCC.

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Cancer research communications

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