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
NAC1 促进三阴性乳腺癌的干性并调节髓系衍生细胞状态
英文原题：NAC1 promotes stemness and regulates myeloid-derived cell status in triple-negative breast cancer.
查看英文原题
NAC1 promotes stemness and regulates myeloid-derived cell status in triple-negative breast cancer.
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中文摘要
三阴性乳腺癌（TNBC）是一种尤其致命的乳腺癌（BC）亚型，由癌症干细胞（CSCs）和免疫抑制微环境驱动。我们的研究揭示，伏隔核相关蛋白1（NAC1），作为BTB/POZ基因家族的一员，在TNBC中发挥关键作用，维持肿瘤干性并影响髓源性抑制细胞（MDSCs）。NAC1高表达与TNBC预后较差相关。敲低NAC1可降低CSC标志物以及肿瘤细胞增殖、迁移和侵袭。此外，NAC1影响致癌通路，如CD44-JAK1-STAT3轴和免疫抑制信号（TGFβ、IL-6）。有趣的是，NAC1对肿瘤生长的影响随宿主免疫状态而变化，在自然杀伤（NK）细胞功能正常的小鼠中表现出致瘤性降低，而在NK细胞缺陷的小鼠中致瘤性增加。这凸显了宿主免疫系统在TNBC进展中的重要作用。此外，MDSCs中高水平的NAC1也支持TNBC干性。总之，本研究提示NAC1是一个有前景的治疗靶点，能够同时清除CSCs并减轻免疫逃逸。
展开英文摘要原文
Triple negative breast cancer (TNBC) is a particularly lethal breast cancer (BC) subtype driven by cancer stem cells (CSCs) and an immunosuppressive microenvironment.
Our study reveals that nucleus accumbens associated protein 1 (NAC1), a member of the BTB/POZ gene family, plays a crucial role in TNBC by maintaining tumor stemness and influencing myeloid-derived suppressor cells (MDSCs). High NAC1 expression correlates with worse TNBC prognosis. NAC1 knockdown reduced CSC markers and tumor cell proliferation, migration, and invasion.
Additionally, NAC1 affects oncogenic pathways such as the CD44-JAK1-STAT3 axis and immunosuppressive signals (TGFβ, IL-6). Intriguingly, the impact of NAC1 on tumor growth varies with the host immune status, showing diminished tumorigenicity in natural killer (NK) cell-competent mice but increased tumorigenicity in NK cell-deficient ones. This highlights the important role of the host immune system in TNBC progression.
In addition, high NAC1 level in MDSCs also supports TNBC stemness.
Together, this study implies NAC1 as a promising therapeutic target able to simultaneously eradicate CSCs and mitigate immune evasion.
论文信息
- 作者
- Ngule C、Shi R、Ren X、Jia H、Oyelami F、Li D、Park Y、Kim J
- 第一作者单位
- Department of Toxicology and Cancer Biology, Department of Pharmacology and Nutritional Science, and Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, 40536, USA.United States
- 通讯作者单位
- Department of Toxicology and Cancer Biology, Department of Pharmacology and Nutritional Science, and Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, 40536, USA. jyang@uky.edu.United States
- 文献类型
- 美国 NIH 资助研究
- 期刊
- Molecular cancer2024 Sep 6
- 原文标识
- PubMed 39243032 · DOI 10.1186/s12943-024-02102-y
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