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
ASCT2 高表达卵巢癌细胞分泌的 IL17A/F 通过激活 c-JUN/PTGS2 通路抑制自然杀伤（NK）细胞细胞毒性促进免疫逃逸
英文原题：IL17A/F secreted by ASCT2-overexpression ovarian cancer cells contributes to immune escape through the suppression of natural killer (NK) cells cytotoxicity by the activation of c-JUN/ PTGS2 pathway.
查看英文原题
IL17A/F secreted by ASCT2-overexpression ovarian cancer cells contributes to immune escape through the suppression of natural killer (NK) cells cytotoxicity by the activation of c-JUN/ PTGS2 pathway.
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中文摘要
卵巢癌（OC）是一种致命的妇科癌症，与转移、复发和治疗耐药相关。丙氨酸-丝氨酸-半胱氨酸转运体2（ASCT2）的表达与OC肿瘤的不良预后和免疫细胞浸润相关，但其潜在机制尚不清楚。使用慢病毒构建体操纵OC细胞（SKOV-3）中ASCT2的表达。使用多种实验方法评估ASCT2对SKOV-3行为的影响，包括增殖、侵袭、迁移、凋亡和细胞周期。使用癌症基因组图谱（TCGA）数据库分析ASCT2表达与OC免疫浸润之间的相关性。进行共培养实验以评估SKOV-3中ASCT2过表达对NK细胞的影响，随后进行转录组学和细胞因子分析。使用qPCR和western blotting表征ASCT2表达和细胞因子水平。ASCT2过表达显著促进细胞增殖、侵袭、迁移和G1期细胞百分比，同时抑制凋亡。ASCT2沉默具有相反的效果。ASCT2的表达与OC中的NK细胞呈负相关。SKOV-3细胞中ASCT2过表达导致IL-17A/F产生过多并抑制NK细胞的抗肿瘤活性，可能通过激活IL-17信号通路。该通路中的核心调控基因c-JUN/PTGS2上调，共培养NK细胞中的抗肿瘤细胞因子减少，导致肿瘤内抗肿瘤活性和免疫浸润降低。
我们的结果表明，ASCT2过表达可能在OC和肿瘤内NK细胞免疫浸润中发挥主要作用。
展开英文摘要原文
Ovarian cancer (OC) is a deadly gynecologic cancer associated with metastasis, recurrence, and treatment resistance. The expression of the alanine-serine-cysteine transporter 2 (ASCT2) has been linked to poor prognosis and immune cell infiltration in OC tumors, but the underlying mechanisms are unclear. Lentiviral constructs were used to manipulate ASCT2 expression in OC cells (SKOV-3). The effects of ASCT2 on SKOV-3 behaviors including proliferation, invasion, migration, apoptosis, and cell cycle were assessed using various assays. The correlation between ASCT2 expression and immune infiltration in OC was analyzed using the Cancer Genome Atlas (TCGA) database. Co-culture experiments were conducted to evaluate the impact of ASCT2 overexpression in SKOV-3 on NK cells, followed by transcriptomics and cytokine analysis.
ASCT2 expression and cytokine levels were characterized using qPCR and western blotting. ASCT2 overexpression significantly promoted cell proliferation, invasion, migration, and the percentage of G1-phase cells, while inhibiting apoptosis. ASCT2 silencing had the opposite effect. The expression of ASCT2 was negatively associated with NK cells in OC.
ASCT2 overexpression in SKOV-3 cells led to excessive IL-17A/F production and inhibited the antitumor activity of NK cells, possibly through activating the IL-17 signaling pathway. The core regulatory genes c-JUN/PTGS2 in this pathway were upregulated, and antitumor cytokines were decreased in co-cultured NK cells, resulting in decreased antitumor activity and immune infiltration within the tumor.
Our results suggest that overexpression of ASCT2 may play a predominant role in OC and NK cell immune infiltration within the tumor.
论文信息
- 作者
- Zhang H、Li H、Qi Y、He J、Deng L、Chen S、Pan H、Guo H
- 第一作者单位
- Department of Gynaecology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China; Library, Kunming Medical University, No.1168 West Chunrong Road, Chenggong District, Kunming, Yunnan 650500, China.China
- 通讯作者单位
- Department of Gynaecology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China. Electronic address: guohuiming@kmmu.edu.cn.China
- 期刊
- International immunopharmacology2025 Mar 26
- 原文标识
- PubMed 39954656 · DOI 10.1016/j.intimp.2025.114226