ADAR1 通过 cIAP2-NF-κB 信号和 C16orf46 编辑调控食管鳞状细胞癌的放射敏感性
ADAR1 regulates radiosensitivity in ESCC through cIAP2-NF-κB signaling and C16orf46 editing.
作者
作者单位
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China.
- Al - Nasiriyah Teaching Hospital, Nasiriyah, Thi Qar Health Directorate, Iraq.
- Institute of Medical Science, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
- Department of Pathology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China.
- School of Biomedical Sciences and Shandong Medicinal and Biotechnology Center, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China.
摘要
中文
食管鳞状细胞癌（ESCC）经常表现出对放疗的抵抗，限制了治疗效果。我们研究了 RNA 编辑酶 ADAR1（腺苷脱氨酶作用于 RNA）在调节放射敏感性中的作用，使用患者样本、ESCC 细胞系和异种移植模型。ADAR1 在 ESCC 中高表达，并与新辅助放化疗反应不良相关。ADAR1 缺失抑制了肿瘤生长并在体外和体内增强了放射敏感性。ADAR1 耗竭促进了 gasdermin E（GSDME）介导的焦亡，从而致敏肿瘤细胞对照射。全转录组 RNA 编辑分析确定了 C16orf46（16 号染色体开放阅读框 46）为 ADAR1 依赖的功能性编辑靶点，C16orf46 的编辑减少促进了放射增敏。ADAR1 耗竭还改变了 cIAP2（细胞凋亡抑制蛋白 2）和 NF-κB 信号，提示存在一种额外的 RNA 编辑非依赖机制。这些发现将 ADAR1 依赖的 RNA 编辑确定为 ESCC 放疗反应的调节因子，并支持 ADAR1 作为放射增敏的潜在靶点。
English
Esophageal squamous cell carcinoma (ESCC) frequently exhibits resistance to radiotherapy, limiting treatment efficacy. We investigated the role of an RNA-editing enzyme, adenosine deaminase acting on RNA (ADAR1), in regulating radiosensitivity, using patient samples, ESCC cell lines, and xenograft models. ADAR1 showed high expression in ESCC and was associated with a poor response to neoadjuvant chemoradiotherapy. ADAR1 loss suppressed tumor growth and enhanced radiosensitivity in vitro and in vivo. ADAR1 depletion promoted gasdermin E (GSDME)-mediated pyroptosis, thereby sensitizing tumor cells to irradiation. Transcriptome-wide RNA-editing analysis identified C16orf46 (chromosome 16 open reading frame 46) as a functionally relevant ADAR1-dependent editing target, and reduced editing of C16orf46 contributed to radiosensitization. ADAR1 depletion also altered cIAP2 (cellular inhibitor of apoptosis protein 2) and NF-κB signaling, suggesting an additional RNA editing-independent mechanism. These findings identify ADAR1-dependent RNA editing as a regulator of ESCC radiotherapy response and support ADAR1 as a potential target for radiosensitization.
分类与指标
- 研究类型
- 基础研究
- 病种
- 食管癌
- JCR 分区
- Q1
- 影响因子
- 4.5
- 新锐分区
- 3区