核TOP1MT通过HNSCC中的伪基赋予了西斯普拉丁耐药性
T Tong1,2,3,4,5,6,7,8, P S Zhai1,2,3,4,5,6, X Qin1,2,3,4,5,6
1Department of Oral and Maxillofacial-Head & Neck Oncology, Shanghai Ninth People's Hospital.
Journal of dental research
|October 9, 2024
概括
线粒体TOP1MT核转移驱动了头癌中西斯白耐药性的驱动,通过伪基CERNA机制增强OXPHOS,提供了新的治疗点.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 生物化学 生物化学
背景情况:
- 西斯普拉丁耐药性显著限制了头部和部状细胞癌 (HNSCC) 的治疗疗效.
- 对于开发新型治疗策略至关重要的是了解基底的分子机制.
研究的目的:
- 确定关键的分子参与者和参与HNSCC. cisplatin耐药性的途径.
- 阐明线粒体拓酶I (TOP1MT) 在赋予西斯抗药性方面的作用.
主要方法:
- 定量蛋白质组学用于识别差异性蛋白质.
- 激光共聚焦显微镜和核细胞质分离试验用于蛋白质定位.
- 染色体免疫沉降测序,双露西法酶记者测定和RNA免疫沉降来研究分子相互作用.
- 在HNSCC模型中的体内和体外实验.
主要成果:
- TOP1MT被确定为HNSCC中西斯普拉丁耐药性的关键驱动因素.
- TOP1MT转移到细胞核 (nTOP1MT) 在耐思白细胞中.
- nTOP1MT通过转录激活了假基因MTATP6P1,该假基因作为miR-137和miR-491-5p的竞争性内源RNA (ceRNA) 起作用.
- 这种ceRNA机制增加了MTATP6的表达,增强了线粒体的氧化酸化 (OXPHOS) 并促进了对西斯普拉丁的抗性.
结论:
- 核TOP1MT激活MTATP6P1,从而通过ceRNA网络增加MTATP6的表达.
- 增强的OXPHOS有助于在HNSCC中对西斯普拉丁的耐药性.
- 这项研究揭示了一种新型的西斯普拉丁耐药性机制,并确定nTOP1MT作为潜在的治疗点.
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