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VHL突变驱动人类清细胞细胞癌的进展,通过PI3K/AKT依赖的胆固醇积积累

Shuo Zhang¹, Tinghe Fang¹, Yexuan He¹

¹Key Laboratory of Biomechanics and Mechanobiology (Beihang University), Ministry of Education, Institute of Medical Photonics, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100191, China.

|April 2, 2024

概括

清细胞细胞癌 (ccRCC) 呈现胆固醇 (CE) 积累,由VHL突变驱动. 抑制胆固醇化抑制了ccRCC的攻击性,提供了一个新的治疗策略.

科学领域:

在瘤学瘤学.
生物化学生化学
分子生物学分子生物学

背景情况:

胆固醇 (CE) 在细胞内脂滴 (LD) 中的积累是清细胞细胞癌 (ccRCC) 的标志.
在ccRCC中CE积累的精确分子机制和病理意义在很大程度上是未知的.
通常使用的ccRCC细胞系往往缺乏在患者组织中观察到的具有特征的CE丰富脂质特征.

研究的目的:

调查ccRCC中CE积累的分子驱动因素和病理作用.
为研究ccRCC脂质代谢建立可靠的体外和体内模型.
探索针对ccRCC中的胆固醇化治疗的治疗潜力.

主要方法:

使用无标签拉曼光谱显微镜 (结合刺激拉曼散射显微镜和共聚焦拉曼光谱) 来对ccRCC细胞和组织中的LD进行现场分析.
从人体组织中分离出初级ccRCC细胞,以准确建模CE丰富的表型.
开发了一种患者衍生的异种移植 (PDX) 鼠标模型,该模型总结了人类ccRCC的CE丰富特征.

主要成果:

发现VHL (von Hippel-Lindau) 突变,这是ccRCC中常见的遗传变异,诱导CE积累.
证明VHL突变可以调节HIFα (低氧诱导因子α) 并激活PI3K/AKT/mTOR/SREBPs通路,促进CE积累.
通过抑制整合素和MAPK信号通路,显示抑制胆固醇化可显著降低cccRCC的侵略性在体外和体内,毒性最小,通过降低整合素和MAPK信号通路.

结论:

这项研究阐明了CE积累在ccRCC发病过程中的关键作用,将其与VHL突变和特定信号通路联系起来.
向胆固醇化为ccRCC提供了一个有前途且耐受良好的治疗策略.
这些发现提高了对ccRCC脂质代谢的理解,并为临床干预提供了新的途径.

关键词:

胆固醇的新陈代谢清细胞脏细胞癌.拉曼光谱显微镜的使用刺激的拉曼散射显微镜.这是一种VHL突变.

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