结直肠癌细胞中的LAT1表达对实验性缺氧下HIF-1/2α积累无反应
Ryuichi Ohgaki1,2, Yuma Hirase3, Minhui Xu3
1Department of Bio-System Pharmacology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan. ohgaki@pharma1.med.osaka-u.ac.jp.
Scientific reports
|August 23, 2024
概括
低氧诱导因子 (HIFs) 不会在结直肠癌细胞中的L型氨基酸载体1 (LAT1) 上调,这与其他癌症相反. 然而,抑制HIF降解可以增加LAT1的表达,这表明复杂的调节.
科学领域:
- 分子生物学分子生物学
- 癌症研究 癌症研究
- 细胞生物学 细胞生物学
背景情况:
- L型氨基酸载体1 (LAT1) 对于癌症进展至关重要,并且在各种癌症中被上调.
- 缺氧诱导因子 (HIF) 是已知的在缺氧条件下基因表达的调节者.
- 在结直肠癌 (CRC) 中,HIFs在LAT1调节中的作用仍然未被研究,尽管LAT1在CRC中的预后意义重大.
研究的目的:
- 在低氧条件下调查结直肠癌细胞中HIF和LAT1表达之间的调控关系.
- 探索控制CRC中LAT1表达的替代机制,特别是对氨基酸可用性和HIF稳定性的反应.
主要方法:
- 在低氧 (1% O2) 和正常的条件下培养人类结直肠癌细胞系 (HT-29和其他八种细胞系).
- 通过RT-qPCR和西式涂抹评估LAT1mRNA和蛋白质水平.
- 诱导氨基酸限制以评估LAT1反应.
- 利用Hippel-Lindau (VHL) 的ubiquitin结合酶 knockdown来稳定HIFs并观察对LAT1表达的影响.
主要成果:
- 低氧并没有诱导HT-29细胞中的LAT1mRNA或蛋白质,尽管HIF-1/2α积累和葡萄糖载体1上调.
- 低毒性治疗通常未能在八个测试的CRC细胞系中增加LAT1表达.
- 氨基酸限制显著提高了LAT1表达的调节.
- VHL的淘汰导致HIF-2α的积累,并增加了特定CRC细胞系中的LAT1表达.
结论:
- 对LAT1的依赖于HIF的转录上调并不是结直肠癌中的通用机制.
- 在CRC中,LAT1表达受到氨基酸可用性而不是缺氧的显著调节.
- 抑制HIF蛋白质体降解在某些CRC环境中为LAT1上调提供了替代途径,突出了监管的复杂性.
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