在基底类乳腺癌和免疫调节中MSH2和MLH1的不同作用
bioRxiv : the preprint server for biology
|September 25, 2023
概括
不匹配修复 (MMR) 基因在基底类乳腺癌 (BLBC) 中具有截然不同的作用. 缺少MSH2通过调节干扰素信号的上升来减少转移,挑战MMR.
科学领域:
- 分子生物学分子生物学
- 在瘤学瘤学.
- 免疫学 免疫学 免疫学
背景情况:
- 不匹配修复 (MMR) 途径以其瘤抑制功能而闻名,MMR基因的突变在遗传性癌症中很常见.
- 在乳腺癌的进展和转移中,MMR基因 (如MSH2和MLH1) 的特定作用仍然在很大程度上未被描述.
研究的目的:
- 研究MSH2和MLH1在基底类乳腺癌 (BLBC) 进展和转移中的功能.
- 阐明MSH2和MLH1影响乳腺癌转移和瘤微环境的分子机制.
主要方法:
- 在BLBC患者队列中分析MSH2和MLH1表达.
- 在小鼠模型中对MSH2和MLH1进行遗传删除研究,以评估转移潜力.
- 研究MSH2和MLH1与IFNAR1促进体结合及其对基因表达和免疫信号的影响.
主要成果:
- MSH2在BLBC中高度丰富,与整体存活率相反相关;其删除减少了转移.
- 删除MLH1增强了肝脏和肺部转移,与MSH2的影响形成鲜明对比.
- MSH2抑制干扰素α受体1 (IFNAR1) 的表达,其删除可调节IFNAR1的表达,激活1型干扰素信号传递,并创造一个免疫活性瘤微环境.
结论:
- MSH2和MLH1在BLBC转移中表现出对立的作用,挑战了MMR途径的普遍瘤抑制范式.
- 由MSH2和MLH1对IFNAR1的不同调节是它们对BLBC进展和免疫微环境调节的不同影响的基础.
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