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
PTEN 恢复和 CXCR2 缺失协同增强恩杂鲁胺的效果并抑制骨转移性 CRPC
英文原题：PTEN restoration and CXCR2 depletion synergistically enhance the effect of enzalutamide and inhibit bone metastatic CRPC.
查看英文原题
PTEN restoration and CXCR2 depletion synergistically enhance the effect of enzalutamide and inhibit bone metastatic CRPC.
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中文摘要
方法
为探究第10号染色体上缺失的磷酸酶和张力蛋白同源物（PTEN）缺失及 C-X-C 基序趋化因子受体2（CXCR2）过表达在 Enz 耐药性 CRPC 和 BmCRPC 中的作用，我们构建了一种具有高骨亲和力的双膦酸盐（BP）类脂质材料（GB4-BPL），用于将 PTEN 质粒（pPTEN）和 CXCR2 siRNA（siCXCR2）共递送至 BmCRPC。
结果
GB4-BPL 的骨转移靶向能力是 GB4-lipo（未进行双膦酸盐修饰）的两倍，同时保持与 Lipo8000 相当的基因转染效率，且细胞毒性显著更低。此外，负载于 GB4-BPL 中的 siCXCR2 和 pPTEN（GB4-BPL@siCXCR2/pPTEN）协同抑制肿瘤生长和转移，在 Enz 耐药模型中使 Enz 的疗效提高了 69.45%。此外，GB4-BPL@siCXCR2/pPTEN 使 MDSCs、Tregs 和 M2 样 TAMs 的数量分别显著减少 55.01%、64.75% 和 52.53%，同时使 M1 巨噬细胞、NK 细胞和 CD8+ T 细胞的比例分别增加 1.65 倍、1.40 倍和 4.60 倍。此外，该纳米系统减少了骨骼相关事件。
结论
我们的研究表明 GB4-BPL 具有将 siCXCR2/pPTEN 递送至肿瘤和骨转移部位的潜力。GB4-BPL@siCXCR2/pPTEN 单独或与 Enz 联合使用可为耐药性 BmCRPC 的治疗提供新策略。
展开英文摘要原文
Rationale: Enzalutamide (Enz) is the first-line therapy for castration-resistant prostate cancer (CRPC).
However, drug resistance has hindered its further application.
Moreover, CRPC is frequently prone to metastasis, particularly to bone (BmCRPC). Methods: To investigate the involvement of phosphatase and tensin homolog deleted on chromosome 10 ( PTEN ) deletion and C-X-C motif chemokine receptor 2 (CXCR2) overexpression in Enz-resistant CRPC and BmCRPC, we constructed a bisphosphonate (BP) lipid-like material with high bone affinity (GB4-BPL) for the codelivery of a PTEN plasmid (pPTEN) and CXCR2 siRNA (siCXCR2) to BmCRPC.
Results: GB4-BPL demonstrated twice the bone metastasis-targeting ability of GB4-lipo (which lacks bisphosphonate modification) while maintaining a gene transfection efficiency comparable to that of Lipo8000 and exhibiting significantly lower cytotoxicity.
Moreover, siCXCR2 and pPTEN loaded in GB4-BPL (GB4-BPL@siCXCR2/pPTEN) synergistically inhibited tumor growth and metastasis, highly enhancing the effect of Enz by 69. 45% in the Enz-resistant model.
Furthermore, GB4-BPL@siCXCR2/pPTEN significantly reduced the numbers of MDSCs, Tregs, and M2-like TAMs by 55. 01%, 64. 75%, and 52. 53%, respectively, while increasing the proportions of M1 macrophages, NK cells, and CD8 + T cells by 1. 65-, 1. 40-, and 4. 60-fold, respectively.
In addition, this nanosystem reduced skeletal-related events. Conclusions: Our studies demonstrated the potential of GB4-BPL for delivering siCXCR2/pPTEN to tumor and bone metastatic sites. GB4-BPL@siCXCR2/pPTEN alone or in combination with Enz could provide a new strategy for the treatment of drug-resistant BmCRPC.
论文信息
- 作者
- Chen J、Gong L、Cao S、Song G、Peng Y、Wang Y、Lou YR、Murtola TJ
- 单位
- School of Pharmaceutical Sciences, Fudan University, Shanghai 201203, China.China
- 期刊
- Theranostics2025
- 原文标识
- PubMed 40860155 · DOI 10.7150/thno.114534
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