VHL L169P 变体在清细胞细胞癌中不会改变细胞低氧张力
Junhui Hu1,2, Desmond J Smith1,3, Lily Wu1,2,4
1Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA.
International journal of molecular sciences
|September 28, 2023
概括
在清晰细胞癌 (ccRCC) 中发现的L169P von Hippel-Lindau (VHL) 变体,表现出与野生型VHL类似的稳定性和功能. 这表明,单独L169P VHL不太可能导致零星的ccRCC瘤发生.
科学领域:
- 瘤发生的发生因子.
- 分子生物学分子生物学
- 遗传学 是一个遗传学.
背景情况:
- ·希佩尔-林道 (VHL) 瘤抑制基因的误解变异在清细胞癌 (ccRCC) 中很常见.
- 由于结构知识有限,许多VHL误解突变的功能影响仍然不清楚.
- 在攻击性,转移性ccRCC病例中发现了L169P变异.
研究的目的:
- 在生物化学和功能上描述L169P VHL误解变体.
- 评估L169P VHL对低氧相关基因表达和ccRCC细胞生长的影响.
- 确定L169P VHL是否有助于零星的ccRCC瘤发生.
主要方法:
- 转导VHL缺乏ccRCC细胞系 (786-O,RCC4) 与表达野生型 (WT) 或L169PVHL的lentiviral载体.
- 对VHL蛋白稳定性和VHL,HIF1α和HIF2α的表达水平的分析.
- 使用mRNA测序 (RNAseq) 来评估缺氧基因表达和计算缺氧得分.
- 在体外和体内细胞增殖的评估 (CAM异种移植).
主要成果:
- L169P VHL表现出与WT VHL相似的蛋白质稳定性.
- 在WT和L169P VHL之间的HIF1α和HIF2α降解中没有发现显著差异.
- 对表达WT或L169PVHL的细胞来说,低毒性得分和细胞增殖率相似.
- 无论是WT还是L169P,VHL都抑制了ccRCC细胞的生长在体外和体内.
结论:
- L169P VHL变体在蛋白质稳定性,HIF降解和缺氧基因调节方面与WT VHL具有功能相似性.
- L169P VHL有效地抑制了ccRCC瘤细胞的生长.
- 这种L169P VHL变异不太可能是零星的ccRCC中瘤发生的唯一驱动因素.
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