胰岛素样生长因子结合蛋白 3 通过 NF-κB/IL-6/ROS 信号的正反馈促进口腔鳞状细胞癌细胞的放射敏感性。
Insulin-like growth factor binding protein 3 promotes radiosensitivity of oral squamous cell carcinoma cells via positive feedback on NF-κB/IL-6/ROS signaling.
机构信息
National Institute of Cancer Research, National Health Research Institutes, 35, Keyan Road, Zhunan Town, Miaoli County, 35053, Taiwan.
Department of Otolaryngology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan.
出版信息
J Exp Clin Cancer Res. 2021 Mar 13;40(1):95. doi: 10.1186/s13046-021-01898-7.
BACKGROUND
Ectopic insulin-like growth factor binding protein 3 (IGFBP3) expression has been shown to enhance cell migration and lymph node metastasis of oral squamous cell carcinoma (OSCC) cells. However, OSCC patients with high IGFBP3 expression had improved survival compared with those with low expression. Therefore, we speculated that IGFBP3 expression may play a role in response to conventional OSCC therapies, such as radiotherapy.
METHODS
We used in vitro and in vivo analyses to explore IGFBP3-mediated radiosensitivity. Reactive oxygen species (ROS) detection by flow cytometry was used to confirm IGFBP3-mediated ionizing radiation (IR)-induced apoptosis. Geneset enrichment analysis (GSEA) and ingenuity pathway analysis (IPA) were used to analyze the relationship between IGFBP3 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling. Assays involving an NF-κB inhibitor, ROS scavenger or interleukin 6 (IL-6) were used to evaluate the NF-κB/IL-6/ROS signaling in IGFBP3-mediated radiosensitivity.
RESULTS
Ectopic IGFBP3 expression enhanced IR-induced cell-killing in vitro. In vivo, IGFBP3 reduced tumor growth and increased apoptotic signals of tumor tissues in immunocompromised mice treated with IR. Combined with IR, ectopic IGFBP3 expression induced mitochondria-dependent apoptosis, which was apparent through mitochondrial destruction and increased ROS production. Ectopic IGFBP3 expression enhanced NK-κB activation and downstream cytokine expression. After IR exposure, IGFBP3-induced NF-κB activation was inhibited by the ROS scavenger N-acetyl-L-cysteine (NAC). IGFBP3-mediated ROS production was reduced by the NF-κB inhibitor BMS-345541, while exogenous IL-6 rescued the NF-κB-inhibited, IGFBP3-mediated ROS production.
CONCLUSIONS
Our data demonstrate that IGFBP3, a potential biomarker for radiosensitivity, promotes IR-mediated OSCC cell death by increasing ROS production through NF-κB activation and cytokine production.
背景
已证实异位胰岛素样生长因子结合蛋白 3（IGFBP3）的表达可增强口腔鳞状细胞癌（OSCC）细胞的迁移和淋巴结转移。然而，IGFBP3 高表达的 OSCC 患者的生存率高于低表达的患者。因此，我们推测 IGFBP3 的表达可能在常规 OSCC 治疗中发挥作用，如放疗。
方法
我们使用体外和体内分析来探讨 IGFBP3 介导的放射敏感性。通过流式细胞术检测活性氧（ROS）来确认 IGFBP3 介导的电离辐射（IR）诱导的细胞凋亡。使用基因集富集分析（GSEA）和 IPA 分析 IGFBP3 与核因子 kappa-轻链增强子的 B 细胞（NF-κB）信号之间的关系。使用 NF-κB 抑制剂、ROS 清除剂或白细胞介素 6（IL-6）进行测定，以评估 IGFBP3 介导的放射敏感性中的 NF-κB/IL-6/ROS 信号。
结果
异位 IGFBP3 表达增强了体外 IR 诱导的细胞杀伤。在体内，IR 治疗后，IGFBP3 减少了免疫缺陷小鼠肿瘤的生长并增加了肿瘤组织的凋亡信号。与 IR 联合使用时，异位 IGFBP3 表达诱导了线粒体依赖性凋亡，这通过线粒体破坏和 ROS 产生增加而明显。异位 IGFBP3 表达增强了 NF-κB 的激活和下游细胞因子的表达。IR 暴露后，ROS 清除剂 N-乙酰-L-半胱氨酸（NAC）抑制 IGFBP3 诱导的 NF-κB 激活。NF-κB 抑制剂 BMS-345541 降低了 IGFBP3 介导的 ROS 产生，而外源性 IL-6 挽救了 NF-κB 抑制的、IGFBP3 介导的 ROS 产生。
结论
我们的数据表明，IGFBP3 作为一种潜在的放射敏感性生物标志物，通过 NF-κB 激活和细胞因子产生增加 ROS 产生，促进了 IR 介导的 OSCC 细胞死亡。
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