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
以纳米颗粒靶向治疗 circTNK2 可恢复 ER 阳性乳腺癌对他莫昔芬的敏感性并增强 NK 细胞介导的免疫
英文原题：Therapeutic targeting of circTNK2 with nanoparticles restores tamoxifen sensitivity and enhances NK cell-mediated immunity in ER-positive breast cancer.
查看英文原题
Therapeutic targeting of circTNK2 with nanoparticles restores tamoxifen sensitivity and enhances NK cell-mediated immunity in ER-positive breast cancer.
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中文摘要
内分泌耐药是雌激素受体（ER）阳性乳腺癌（ER + BC）患者复发的主要原因，其中他莫昔芬耐药是最普遍的形式。circTNK2是一种环状RNA，在他莫昔芬耐药的BC组织中过表达，并与不良预后相关。circTNK2编码一种新的487个氨基酸的蛋白质，称为C-TNK2-487aa，其抑制自然杀伤（NK）细胞向BC肿瘤的募集。在机制上，C-TNK2-487aa与STAT3相互作用并促进ER + BC细胞中STAT3磷酸化（p-STAT3）。增加的p-STAT3与STAT1结合竞争，抑制诱导CXCL10表达的STAT1同源二聚体的形成，最终导致免疫逃逸。
此外，circTNK2 RNA与SRSF1结合，并通过激活AKT-mTOR信号促进他莫昔芬耐药和BC致瘤性。递送负载circTNK2反义寡核苷酸（ASOs）和编码CXCL10的质粒DNA的BC靶向ZIF-8纳米颗粒显著抑制BC肿瘤异种移植物的生长，恢复他莫昔芬敏感性，并增加CD56 + NK细胞向BC肿瘤的浸润。
我们的数据描述了circTNK2编码的肽及其RNA在ER + BC对他莫昔芬耐药和免疫逃逸中的关键作用，为治疗他莫昔芬耐药乳腺癌提供了治疗脆弱性。
展开英文摘要原文
Endocrine resistance is a leading cause of relapse in patients with estrogen receptor (ER)-positive breast cancer (ER + BC), with tamoxifen resistance being the most prevalent form. circTNK2, a circular RNA, is overexpressed in tamoxifen-resistant BC tissues and is correlated with poor prognosis. circTNK2 encodes a novel 487-amino acid protein, termed C-TNK2-487aa, which inhibits the recruitment of natural killer (NK) cells into BC tumors.
Mechanistically, C-TNK2-487aa interacts with STAT3 and promotes STAT3 phosphorylation (p-STAT3) in ER + BC cells. The increased p-STAT3 competes with STAT1 binding, inhibiting the formation of STAT1 homodimers that induces CXCL10 expression, ultimately leading to immune evasion.
Additionally, circTNK2 RNA binds to SRSF1 and promotes tamoxifen resistance and BC tumorigenicity by activating AKT-mTOR signaling. Delivery of BC-targeting ZIF-8 nanoparticles loaded with circTNK2 antisense oligonucleotides (ASOs) and a CXCL10-encoding plasmid DNA markedly suppresses the growth of BC tumor xenografts, restores tamoxifen sensitivity, and increases CD56 + NK cell infiltration into BC tumors.
Our data describe a critical role of the circTNK2-encoded peptide and its RNA in ER + BC resistance to tamoxifen and immune evasion, providing a therapeutic vulnerability in treating tamoxifen-resistant breast cancer.
论文信息
- 作者
- Wu R、Yu S、Bi A、Li Y、Tiek D、Yu K、Xiong H、Shi Q
- 第一作者单位
- Department of Breast Disease Center, General Surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China; The Ken & Ruth Davee Department of Neurology, The Lou and Jean Malnati Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA; Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China.China
- 通讯作者单位
- Department of Breast Disease Center, General Surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China; Department of Blood Transfusion, Key Laboratory of Jiangxi Province for Transfusion Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China; Postdoctoral Innovation Practice Base, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China. Electronic address: zhoubx@ncu.edu.cn.China
- 期刊
- Cancer letters2025 Sep 1
- 原文标识
- PubMed 40419081 · DOI 10.1016/j.canlet.2025.217823