在膀癌中,IRE1α通过ER压力调节调节M1瘤病毒的敏感性
Cheng Hu1,2, Song Wei1,2, Wenbo Zhu3,2
1Department of Urology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, Guangdong, China.
Cancer drug resistance (Alhambra, Calif.)
|August 22, 2025
概括
抑制IRE1α可通过增加内分泌网膜应激和M1病毒诱导的亡来增强肌肉侵袭性膀癌的瘤病毒疗法. 这种策略改善了瘤抑制,并可能提供更好的治疗结果.
科学领域:
- 抗瘤病毒治疗
- 癌症分子生物学
- 膀癌研究
背景情况:
- 肌肉侵入性膀癌 (MIBC) 由于瘤内在的抗药性,因此具有重大治疗挑战.
- 瘤解毒疗法显示出有前途,但由于患者反应的变化而受到限制.
- 了解对瘤病毒分化敏感性的分子机制对于提高疗效至关重要.
研究的目的:
- 研究膀癌中对M1瘤病毒的敏感性变化的分子基础.
- 阐明内质网膜 (ER) 应激和未折叠蛋白质响应 (UPR) 途径,特别是 IRE1α,在M1病毒诱导的细胞死亡中的作用.
- 评估结合M1病毒治疗与IRE1α抑制的治疗潜力.
主要方法:
- 在不同M1敏感性的膀癌细胞系中分析ER压力和UPR激活.
- 使用siRNA和选择性抑制剂 (STF083010) 调节IRE1α表达.
- 在异种移植模型中评估病毒细胞毒性,复制,亡和体内抗瘤功效. 使用患者衍生细胞和TCGA数据探索临床相关性.
主要成果:
- 在敏感细胞系中,M1病毒诱导了ER应激和细胞亡,而不那么敏感的细胞系表现出极小的反应.
- 在中度敏感的细胞中,M1复制导致IRE1α上调,从而减轻了ER应激和亡.
- 在体外,IRE1α抑制增强了M1诱导的ER压力,细胞亡和瘤溶解,并在体内增强了瘤抑制,但没有增加毒性. 患者瘤中的IRE1α降低与预后较差相关.
结论:
- 在膀癌中,IRE1α 作为M1病毒诱导的蛋白质积累和细胞死亡的调节剂.
- 抑制 IRE1α 增强了 ER 压力,并显著增强了 M1 病毒的抗瘤功效.
- 针对IRE1α是一种有前途的策略,可以改善基于M1的病毒治疗结果,特别是在可访问的瘤中.
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