RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
在小鼠乳腺癌模型中，NKp46 与 Syndecan-1 之间的相互作用上调 NK 细胞上 Notch1 和 Notch2 的表达
英文原题：The Expression of Notch1 and Notch2 is Up-Regulated on Natural Killer Cells by the Interaction Between NKp46 and Syndecan-1 in a Mouse Breast Cancer Model.
查看英文原题
The Expression of Notch1 and Notch2 is Up-Regulated on Natural Killer Cells by the Interaction Between NKp46 and Syndecan-1 in a Mouse Breast Cancer Model.
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研究概要
NKp46-Syndecan-1 相互作用促进 Notch1 和 Notch2 表达，从而增强 NK 细胞活性。
研究思路结论见上方概要
背景
乳腺癌的特征是乳腺细胞不受控制地生长并最终形成肿瘤。探究乳腺癌微环境中NK细胞功能的分子机制至关重要。
方法
在小鼠乳腺癌植入模型中，通过流式细胞术、细胞毒性评估、实时PCR、体外共培养、基因修饰肿瘤细胞和NK细胞过继转移，分析了NK细胞中Notch1和Notch2的调控因素。
结果
Notch1和Notch2在肿瘤浸润NK细胞上差异表达，形成Notch1+Notch2+（DP）亚群和Notch1-Notch2-（DN）亚群。DP细胞在活化后表达更高水平的IFN-γ、TNF-α、颗粒酶B、穿孔素和CD107a，从而具有更强的细胞毒性。DP细胞表达更高水平的活化性受体，如NKp46、NKG2D和DNAM-1。与乳腺癌细胞系EMT6共培养可上调Notch1和Notch2。阻断NKp46与其配体的连接可阻止Notch1和Notch2的上调。此外，在Syndecan-1（一种NKp46共配体）敲除的EMT6植入物中，NK细胞表达的IFN-γ、TNF-α、Notch1和Notch2低于表达Syndecan-1的EMT6植入物中的对应细胞，并且抑制EMT6植入物生长的能力较弱。
展开英文摘要原文
BACKGROUND
Breast cancer is characterized by uncontrolled breast cell growth and eventual tumor formation. It is crucial to explore the molecular mechanisms of NK cell function in the breast cancer microenvironment.
METHODS
The regulatory factors of Notch1 and Notch2 in NK cells were analyzed in a mouse breast cancer implantation model using flow cytometry, cytotoxicity evaluation, real-time PCR, in vitro co-culture, genetically modified tumor cells, and adoptive transfer of NK cells.
RESULTS
Notch1 and Notch2 were differentially expressed on tumor-infiltrating NK cells, forming a Notch1+Notch2+ (DP) subset and Notch1-Notch2-(DN) subset. DP cells expressed higher levels of IFN-γ, TNF-α, granzyme B, perforin, and CD107a upon activation, thereby becoming more cytotoxic. DP cells expressed higher levels of activating receptors, such as NKp46, NKG2D, and DNAM-1. Co-culture with the breast cancer cell line EMT6 up-regulated Notch1 and Notch2. Blockage of the ligation of NKp46 to its ligands prevented the up-regulation of Notch1 and Notch2. Moreover, NK cells expressed lower IFN-γ, TNF-α, Notch1, and Notch2 in Syndecan-1 (an NKp46 co-ligand) knockout EMT6 implants than their counterparts in Syndecan-1-expressing EMT6 implants, and were less competent to inhibit EMT6 implant growth.
CONCLUSION
The NKp46-Syndecan-1 interaction promoted Notch1 and Notch2 expression to boost NK cell activity.
论文信息
- 作者
- Wang L、Bie T、He J、Xiao Y、Chen K
- 单位
- Department of Thyroid and Breast Surgery, Wuhan Third Hospital, Wuhan, Hubei Province, China.China
- 期刊
- Immunological investigations2026 Sep 7
- 原文标识
- PubMed 42704223 · DOI 10.1080/08820139.2026.2729083