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无机诱导高的p53水平与改变功能影响表达的收费类受体3和其他目标基因在不朽的前列腺上皮细胞的表达
Nancy C Pacheco-Castillo1, Jesús Gómez-Montalvo2, Vanesa Olivares-Illana3
1Laboratorio de Inmunotoxicología, Facultad de Ciencias Químicas, Universidad Autónoma de San Luis Potosí, San Luis Potosí 78210, Mexico.
International journal of molecular sciences
|May 14, 2025
概括
无机暴露会损害前列腺癌 (PCa) 细胞中瘤抑制器p53的功能,导致关键基因的表达减少,例如Toll-like受体3 (TLR3). 这种机制促进PCa的进展,并建议针对p53活动的治疗策略.
科学领域:
- 在瘤学瘤学.
- 环境健康 环境健康
- 分子生物学分子生物学
背景情况:
- 前列腺癌 (PCa) 是一个重大的全球健康挑战,特别是在晚期.
- 化学疗法耐药性和与雄激素无关的生长限制在晚期PCa的生存率.
- 由p53调节的Toll-like受体3 (TLR3) 是PCa的一个潜在的治疗点.
- 无机 (iAs) 暴露与PCa的进展和TLR3表达的减少有关.
研究的目的:
- 研究慢性无机暴露对前列腺上皮细胞p53功能的影响.
- 确定IAs影响p53转录活性和下游目标基因的机制.
- 探索p53活性受损在IAs诱导的PCa进展中的作用.
主要方法:
- 长期暴露于酸 (NaAsO) 的不朽的前列腺上皮细胞.
- 对p53,TLR3,CDKN1A和BAX基因和蛋白质表达的分析.
- 染色体免疫沉 (ChIP) 来评估p53促进体结合.
- 通过测序进行TP53突变分析.
- 在前列腺腺癌数据中对TP53,TLR3和CDKN1A进行生物信息分析.
主要成果:
- 长期的NaAsO暴露增加了p53转录和蛋白质水平,但减少了p53点基因 (TLR3,CDKN1A,BAX) 的表达.
- 对TLR3和CDKN1A促进体的p53结合减少,这表明p53.3在转录方面不活跃.
- 排除TP53突变作为p53功能障碍的原因.
- 在前列腺腺癌中,生物信息分析显示TP53升高,但TLR3和CDKN1A降低,与IA暴露效应相关.
结论:
- 慢性IA暴露会破坏前列腺细胞中的p53转录活性,可能是通过氧化应激诱导的翻译后或表观遗传修饰.
- 损坏的p53功能通过降低像TLR3.3这样的瘤抑制基因的调节,有助于PCa的进展.
- 恢复p53转录活性代表了PCa患者与IA暴露的潜在治疗策略.
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