在肝细胞癌中被SETDB1抑制的内源逆转录病毒元素的鉴定和临床影响
Yosuke Igarashi1,2, Yoshimitsu Akiyama1, Shu Shimada1
1Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
JHEP reports : innovation in hepatology
|March 10, 2025
概括
在肝癌中,SETDB1抑制人类内源逆转录病毒 (HERVs). 低HERV表达表明预后不佳,而激活这些HERV可能会提供一种新的HCC疗法.
科学领域:
- 表观遗传学和癌症生物学
- 病毒学和免疫学 病毒学和免疫学
背景情况:
- 抑制表观遗传调节剂可以激活内源逆转录病毒 (ERV),可能触发癌细胞中的病毒模仿反应.
- 在肝细胞癌 (HCC) 中观察到异常ERV表达,但其通过基因素修饰的调节和临床意义尚未完全理解.
- 特定的人体内源性逆转录病毒 (HERV) 在HCC中被SETDB1表观遗传抑制的元素被确定.
研究的目的:
- 研究SETDB1在肝细胞癌 (HCC) 中调节HERV表达中的作用.
- 确定SETDB1-调节的HERVs作为HCC的预后标记物的临床意义.
- 探索在HCC中激活SETDB1-调节的HERV的治疗潜力.
主要方法:
- 对癌症基因组图谱 (TCGA) 数据集的分析,以根据SETDB1表达水平识别HERV元素.
- 在小鼠和人类的HCC细胞中进行SETDB1敲除 (KD),以评估生物效应和HERV表达变化.
- 在体外和体内实验评估瘤生长,免疫细胞透和基因表达模式.
主要成果:
- 在人类的HCC中发现了SETDB1和逆元素之间的反向相关性 (R = -0.723,p = 2.297 × 10−40).
- 在SETDB1高的HCC病例中确定了四种特定的HERV元素;低表达与预后不佳相关.
- 在HCC细胞中SETDB1的枯竭导致HERV表达的增加,H3K9me3的减少,干激素刺激基因的升高表明病毒模仿性,以及瘤生长受损,CD8+ T细胞透的增加 in vivo.
结论:
- 通过SETDB1抑制四个HERV元素作为HCC的预后标记.
- 受到SETDB1调节的HERVs代表了HCC的潜在治疗点.
- 这些HERVs的激活可能会诱导病毒模拟反应,提供一个有前途的治疗策略.
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