核 TOP1MT 在 HNSCC 中通过伪基因产生顺铂抗性

T Tong, P S Zhai, X Qin, Z Zhang, C W Li, H Y Guo, H L Ma
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引用次数: 0

摘要

顺铂耐药性是头颈部鳞状细胞癌(HNSCC)治疗失败的主要原因之一。目前迫切需要揭示其潜在机制,以制定有效的治疗策略。本研究采用定量蛋白质组学分析方法来鉴定顺铂耐药细胞中的差异蛋白质。线粒体拓扑异构酶I(TOP1MT)的定位是通过激光共聚焦显微镜和核胞质分离试验确定的。染色质免疫共沉淀测序、双荧光素酶报告分析和 RNA 免疫共沉淀被用来鉴定伪基因、miRNA 和真基因之间的相互作用。体内实验验证了 TOP1MT 与伪基因之间在顺铂抗性上的相互作用。在体外、体内和 HNSCC 患者中,TOP1MT 被确定为顺铂耐药性的驱动因素。此外,在顺铂耐药的 HNSCC 细胞中,TOP1MT 例外地以信号肽依赖的方式转位到细胞核中。核TOP1MT(nTOP1MT)转录调控线粒体功能假基因MTATP6P1,MTATP6P1作为竞争性内源性RNA(ceRNA)与miR-137和miR-491-5p结合,促进MTATP6的表达。MTATP6的增加增强了线粒体氧化磷酸化(OXPHOS),从而赋予了HNSCC顺铂抗性。我们的研究结果表明,nTOP1MT可通过ceRNA转录激活MTAPT6P1并增加MTATP6的表达,从而促进OXPHOS和顺铂抗性。这些结果为克服 HNSCC 的顺铂耐药性提供了新的见解。
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Nuclear TOP1MT Confers Cisplatin Resistance via Pseudogene in HNSCC.

Cisplatin resistance is one of the major causes of treatment failure in head and neck squamous cell carcinoma (HNSCC). There is an urgent need to uncover the underlying mechanism for developing effective treatment strategies. A quantitative proteomics assay was used to identify differential proteins in cisplatin-resistant cells. Mitochondrial topoisomerase I (TOP1MT) localization was determined using laser confocal microscopy and nucleocytoplasmic separation assay. Chromatin immunoprecipitation sequencing, dual-luciferase reporter assay, and RNA immunoprecipitation were used to identify the interaction between pseudogenes, miRNAs, and real genes. In vivo experiments verified the interaction between TOP1MT and pseudogenes on cisplatin resistance. TOP1MT was identified as a driving factor of cisplatin resistance in vitro, in vivo, and in HNSCC patients. Moreover, TOP1MT exceptionally translocated to the nucleus in cisplatin-resistant HNSCC cells in a signal peptide-dependent manner. Nuclear TOP1MT (nTOP1MT) transcriptionally regulated the mitochondrial functional pseudogene MTATP6P1, which bound to miR-137 and miR-491-5p as a competing endogenous RNA (ceRNA) and promoted the expression of MTATP6. An increase in MTATP6 enhanced mitochondrial oxidative phosphorylation (OXPHOS), which conferred cisplatin resistance in HNSCC. Our findings revealed that nTOP1MT transcriptionally activated MTAPT6P1 and increased MTATP6 expression via ceRNA, which facilitated OXPHOS and cisplatin resistance. These results provide novel insight for overcoming cisplatin resistance in HNSCC.

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Oral Health Research in the WHO African Region between 2011 and 2022: A Scoping Review. Advanced Imaging in Dental Research: From Gene Mapping to AI Global Data. A Deep Learning System to Predict Epithelial Dysplasia in Oral Leukoplakia. Nuclear TOP1MT Confers Cisplatin Resistance via Pseudogene in HNSCC. Periodontitis and Diabetes Differentially Affect Inflammation in Obesity.
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