AhR-Siglec-15轴通过TRPML1调节溶酶体Ca2+释放,用于通过TRPML1进行声波刺髓母细胞瘤生长
Zhenfeng Wang1, Shunshun Li2,3, Xu Sun1
1Department of Immunology & State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS, ) & Peking Union Medical College, Beijing, 100005, China.
Protein & cell
|November 19, 2025
概括
声波刺子子组髓母细胞瘤 (SHH-MB) 的增长是由酸结合性免疫球蛋白类受体15 (Siglec-15) 驱动的. 向基碳化合物受体 (AhR) -Siglec-15通路为这种侵袭性儿科脑瘤提供了一个有希望的治疗策略.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 神经科学是一个神经科学.
背景情况:
- 声波刺子子组神经母细胞瘤 (SHH-MB) 是一种侵略性的儿科脑瘤,分子驱动因素不明,导致治疗挑战.
- 酸结合性免疫球蛋白类受体15 (Siglec-15),一种免疫抑制性膜蛋白,已成为瘤进展的潜在因素.
研究的目的:
- 阐明SHH-MB生长背后的分子机制.
- 调查Siglec-15在SHH-MB发展中的作用,并确定潜在的治疗点.
主要方法:
- 在SHH-MB细胞中研究了Siglec-15的表达和局部化.
- 使用了离子独立的曼诺6酸盐受体 (CI-MPR) 途径分析.
- 研究了Siglec-15,粘脂蛋白TRP阴离子通道1 (TRPML1) 和转录因子EB (TFEB) 之间的相互作用.
- 评估阻断Siglec-15,TRPML1或TFEB对体外和体内SHH-MB生长的影响.
- 研究了基碳化合物受体 (AhR) 在调节Siglec-15表达中的作用,并在临床前模型中评估了AhR抑制剂 (CH-223191,SR1).
主要成果:
- 西格莱克-15在SHH-MB上调,并通过CI-MPR转移到溶酶体膜.
- 西格莱克-15与TRPML1相互作用,诱导 lysosomal Ca2+释放和随后的TFEB核转位.
- 抑制Siglec-15,TRPML1或TFEB显著阻碍了SHH-MB的生长.
- 亚利碳化合物受体 (AhR) 调高了Siglec-15的表达.
- 在小鼠中,AhR抑制证明了对SHH-MB异种移植的治疗疗效.
结论:
- AhR-Siglec-15信号轴对于SHH-MB的发展至关重要.
- 向Siglec-15,TRPML1,TFEB或AhR为SHH-MB提供了一个潜在的治疗策略.
- 了解这些分子通路为治疗这种侵袭性儿科脑瘤开辟了新的途径.
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