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戈尔吉局部化环指蛋白121是MYCN驱动的神经母细胞瘤瘤发生所必需的
Belamy B Cheung1,2, Ritu Mittra3, Jayne Murray3
1Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW Sydney, Sydney, Australia. bcheung@ccia.unsw.edu.au.
Communications biology
|October 14, 2024
概括
环指蛋白121 (RNF121) 对MYCN驱动的神经母细胞瘤生长至关重要. 破坏RNF121的功能会阻止瘤的发展,将其确定为这种侵袭性儿童癌症的潜在治疗标.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 遗传学 遗传学 是一个
背景情况:
- MYCN放大是侵略性神经母细胞瘤的关键驱动因素,与患者预后不佳有关.
- 了解MYCN的瘤性依赖对于开发有效的向疗法至关重要.
研究的目的:
- 为了确定MYCN驱动的神经母细胞瘤瘤发生所必需的遗传因素.
- 研究环指蛋白121 (RNF121) 作为潜在的MYCN辅因子的作用.
主要方法:
- 在TH-MYCN转基因小鼠中利用N-乙烯-N-酸氨酸 (ENU) 突变发生,以确定调节神经母细胞瘤发育的基因.
- 进行全基因组测序,以识别损失瘤发生的小鼠中的突变.
- 研究了野生型 (WT) 和突变RNF121与MYCN的亚细胞局部化,蛋白质稳定性和功能相互作用.
主要成果:
- 确定了RNF121基因 (RNF121M158R) 的突变,与神经母细胞瘤瘤发生的遗传性损失有关.
- RNF121WT蛋白定位到戈尔吉综合体,而RNF121M158R突变破坏了定位和稳定.
- 在TH-MYCN瘤中,RNF121WT的表达是上调调的,其删除会降低瘤性;RNF121直接结合并稳定MYCN.
- 高RNF121mRNA水平与人类神经母细胞瘤和喉癌的预后不佳相关.
结论:
- 在神经母细胞瘤中,RNF121是MYCN的必不可少的瘤原因子.
- RNF121与MYCN的相互作用对瘤生长和稳定性至关重要.
- RNF121代表了对MYCN增强神经母细胞瘤和潜在的其他MYC驱动的癌症的有前途的治疗标.
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