TERT通过调节核糖体生物生成来加速BRAF突变诱导的甲状腺癌脱差和进展
Pengcheng Yu1,2,3,4, Ning Qu1,2, Rui Zhu3,4
1Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
Science advances
|August 30, 2023
概括
TERT的重新激活通过增强的核糖体生物生成促进细胞脱差,从而推动甲状腺癌的进展. 抑制核糖体转录为这些侵袭性癌症提供了潜在的治疗策略.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 癌症研究 癌症研究
背景情况:
- 在晚期的人类癌症中,TERT重新激活是常见的,但它在癌症进展中的体内作用和机制尚不清楚.
- 了解TERT的功能对于开发针对性治疗恶性瘤至关重要.
研究的目的:
- 为了研究TERT再激活在甲状腺癌进展中的体内功能.
- 阐明TERT影响瘤发育和异质性的潜在分子机制.
- 探索针对TERT驱动癌症的潜在治疗策略.
主要方法:
- 在甲状腺上皮中产生表达TERT和/或BRAF V600E的基因工程小鼠模型.
- 使用空间转录组分析来评估瘤异质性和细胞特征.
- 研究TERT与参与核糖体生物发生的蛋白质的相互作用.
- 在临床前模型中评估rRNA转录抑制剂 (CX-5461) 的疗效.
主要成果:
- BRAF V600E诱导乳头甲状腺癌,而与TERT的同时表达导致差异化甲状腺癌.
- 表达TERT的瘤表现出显著的异质性,细胞脱差与核糖体生物发生相关.
- 发现TERT通过与核糖体生物发生机制的相互作用来增强核糖体RNA表达和蛋白质合成.
- 在甲状腺癌模型中,CX-5461治疗抑制了瘤扩散,并促进了重新分化.
结论:
- TERT的重新激活通过诱导癌细胞去分化来促进甲状腺癌的进展.
- TERT的机制涉及促进核糖体生物发生和蛋白质合成.
- 抑制核糖体转录为TERT-reactivated甲状腺癌和潜在的其他恶性瘤提供了一个有前途的治疗途径.
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