丢失TP53与c-MET过度表达合作,驱动肝癌发生
Yi Zhou1,2, Guofei Cui2,3, Hongwei Xu2,4
1Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Cell death & disease
|July 27, 2023
概括
在小鼠中,TP53和c-MET激活的损失驱动肝癌 (肝细胞癌). 特拉美替尼布有效地抑制了瘤生长,这表明它有可能用于治疗TP53-突变的人类HCC.
科学领域:
- 肝细胞癌研究 肝细胞癌研究
- 癌症遗传学 癌症遗传学
- 分子瘤学分子瘤学
背景情况:
- 肝细胞癌 (HCC) 呈现出显著的遗传多样性.
- 在HCC中,TP53突变和c-MET激活是常见的.
- 同时的TP53突变和c-MET激活发生在~20%的HCC患者中,与预后不佳相关.
研究的目的:
- 研究TP53损失和c-MET激活在肝癌发生中的合作作用.
- 开发和验证TP53-null HCC. 的临床前模型.
- 在TP53-零HCC模型中评估MEK抑制剂特拉美丁尼的疗效.
主要方法:
- 生成了一个小鼠模型,同时出现Trp53删除和c-MET过度表达 (c-MET/sgp53).
- 利用RNA测序来表征c-MET/sgp53 HCC中的分子变化.
- 从小鼠模型开发和特征HCC细胞系和异种移植.
- 进行了对特拉美丁尼布疗效的体和实验验证.
主要成果:
- 在c-MET/sgp53小鼠模型中,自发地产生了HCC.
- c-MET/sgp53 HCCs显示了激活的c-MET,Ras/MAPK信号,以及增加的扩散.
- 特拉美丁尼 (Trametinib) 显著抑制了c-MET/sgp53 HCC细胞和异种移植的生长.
- 在基分析预测和实验证实了特拉美替尼在TP53-零HCC中的有效性.
结论:
- 丢失TP53与c-MET激活合作,驱动肝癌发生.
- c-MET/sgp53小鼠模型和衍生细胞系是TP53-null HCC研究的宝贵临床前工具.
- 特拉美替尼布在治疗具有TP53-null突变的人类HCC方面显示出治疗潜力.
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