表达:MEF2A通过调节NFKBIA/NF-κB信号通路抑制胃癌细胞的顺铂耐药性

IF 2.5 4区 医学 Q1 MEDICINE, GENERAL & INTERNAL
Journal of Investigative Medicine Pub Date : 2025-01-01 Epub Date: 2024-11-08 DOI:10.1177/10815589241290199
Chenghao Chu, Yongwei Zhang, Ruiran Yu, Bin Liu, Bin Wang, Zhangxuan Xu, Kai Ling Chin
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引用次数: 0

摘要

顺铂(DDP)耐药性是导致胃癌(GC)化疗失败和患者不良预后的关键因素。本研究旨在探讨肌细胞增强因子2A(MEF2A)在胃癌DDP耐药中的作用及其内在机制。研究应用 AGS 和 MKN-45 细胞构建 DDP 耐药细胞。CCK-8、菌落形成和流式细胞术等方法测定了DDP的IC50值和GC细胞的存活率。染色质免疫沉淀和双荧光素酶检测验证了MEF2A和NF-κB抑制剂α(NFKBIA)之间的分子关系。利用异种移植模型研究了 MEF2A 在体内的作用。结果表明,与各自的亲代细胞相比,耐DDP的AGS和MKN-45细胞中NFKBIA的表达量大大降低。NFKBIA表达的增加损害了DDP的IC50值和DDP耐药细胞的存活率,而这些改变在TNF-α处理后得到了挽救。从机理上讲,MEF2A是NFKBIA的转录激活剂,导致p65磷酸化和胞质滞留减少。此外,MEF2A的过表达促进了GC细胞对DDP的敏感性和肿瘤的生长,而NFKBIA的沉默则逆转了这些效应。总之,MEF2A通过调节NFKBIA/NF-κB信号传导缓解了GC细胞对DDP的耐药性,从而揭示了MEF2A/NFKBIA可能是改善GC细胞对DDP耐药性的干预靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
MEF2A restrains cisplatin resistance in gastric cancer cells by modulating NFKBIA/NF-κB signaling pathway.

Cisplatin (DDP) resistance represents a pivotal contributing factor to chemotherapy failure and adverse patient outcomes in gastric cancer (GC). The objective of the present study was to investigate the roles and underlying mechanisms of myocyte enhancer factor 2A (MEF2A) in DDP resistance in GC. GC cell line AGS and MKN-45 cells were applied to construct DDP-resistant cells. CCK-8, colony formation, and flow cytometry methods were validated for determining the IC50 value of DDP and cell survival of GC cells. qRT-PCR and western blotting analysis quantified the molecular levels at mRNA and protein, respectively. Chromatin immunoprecipitation and dual-luciferase assays validated the molecular relationship between MEF2A and NF-κB inhibitor alpha (NFKBIA). Roles of MEF2A in in vivo were performed employing a xenograft model. The results showed that NFKBIA was greatly decreased in DDP-resistant AGS and MKN-45 cells compared to their respective parental cells. Increasing NFKBIA expression impaired the IC50 value of DDP and cell survival in DDP-resistant cells, while these alterations were rescued upon TNF-α treatment. Mechanistically, MEF2A acts as a transcriptional activator of NFKBIA, which led to the reduction of phosphorylation of p65 and cytoplasmic retention. Moreover, MEF2A overexpression promoted the sensitivity of GC cells to DDP and tumor growth, whereas these effects were partially reversed by NFKBIA silence. Collectively, MEF2A mitigated the DDP resistance in GC cells by modulatory actions on the NFKBIA/NF-κB signaling, shedding light on MEF2A/NFKBIA might be a promising intervention target for improving DDP resistance in GC.

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来源期刊
Journal of Investigative Medicine
Journal of Investigative Medicine 医学-医学:内科
CiteScore
4.90
自引率
0.00%
发文量
111
审稿时长
24 months
期刊介绍: Journal of Investigative Medicine (JIM) is the official publication of the American Federation for Medical Research. The journal is peer-reviewed and publishes high-quality original articles and reviews in the areas of basic, clinical, and translational medical research. JIM publishes on all topics and specialty areas that are critical to the conduct of the entire spectrum of biomedical research: from the translation of clinical observations at the bedside, to basic and animal research to clinical research and the implementation of innovative medical care.
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