肿瘤细胞治疗研究
英文原题：Exosomal circPDSS1 Derived From Gastric Cancer Cells Promotes Natural Killer Cell Ferroptosis by Regulating the miR-142-3p/ACSL4 Molecular Axis.
自然杀伤（NK）细胞在对抗胃癌（GC）中发挥关键作用。
自然杀伤（NK）细胞在对抗胃癌（GC）中发挥关键作用，但在GC肿瘤微环境中会发生铁死亡，削弱其抗肿瘤效应。外泌体circRNA可影响GC进展。既往研究报道circPDSS1具有促癌作用，但其是否参与NK细胞铁死亡尚不明确。本研究旨在考察胃癌细胞来源外泌体circPDSS1对NK细胞铁死亡的作用。研究建立胃癌细胞（HGC-27、AGS和MKN-45）与人NK-92细胞的非接触共培养系统，并构建人源化小鼠及细胞来源异种移植（CDX）肿瘤模型进行联合研究。通过流式细胞术、LDH释放和CCK-8实验评估细胞死亡和活力；通过琼脂糖凝胶电泳及放线菌素D处理检测circPDSS1稳定性；通过检测脂质ROS、MDA和Fe²⁺水平评估铁死亡；并采用双荧光素酶报告实验、RIP及RNA pull-down实验确定关键分子相互作用。临床肿瘤组织中CD56和CD16表达降低。体外实验显示，与胃癌细胞共培养后，7-AAD⁺ NK-92细胞比例显著升高，同时细胞死亡增加，IFN-γ和TNF-α分泌减少。进一步研究发现，circPDSS1在胃癌组织和细胞中异常升高，尤其富集于MKN-45细胞来源外泌体。敲低circPDSS1可减轻MKN-45外泌体诱导的细胞损伤，降低NK-92细胞脂质ROS、MDA和Fe²⁺水平，并延缓肿瘤进展。此外，铁死亡抑制剂可抑制circPDSS1过表达诱导的细胞死亡。从机制上看，circPDSS1通过海绵吸附miR-142-3p上调ACSL4表达，促进NK细胞铁死亡。胃癌细胞来源外泌体circPDSS1通过吸附miR-142-3p、提高ACSL4表达促进NK细胞铁死亡，从而加重胃癌。
Natural killer (NK) cells play a crucial role in combating gastric cancer (GC). However, they undergo ferroptosis in the tumor microenvironment of GC, which weakens their antitumor effects. Exosomal circRNA influences GC progression. Previous studies have reported the cancer-promoting role of circPDSS1 in GC, but whether it is involved in NK cell ferroptosis remains unclear. This study aimed to investigate the role of GC cell-derived exosomal circPDSS1 in NK cell ferroptosis. A noncontact coculture system of GC cells (HGC-27, AGS, and MKN-45 cells) and human NK-92 cells was established, and humanized mouse and cell-derived xenograft (CDX) tumor models were constructed for joint investigation. Cell death and viability were assessed via flow cytometry, LDH release assays and CCK-8 assays; circPDSS1 stability was determined by agarose gel electrophoresis and actinomycin D treatment; ferroptosis was determined by measuring lipid ROS, MDA, and Fe 2+ levels; and key molecular interactions were determined by performing dual-luciferase reporter assays and RIP and RNA pull-down experiments. CD56 and CD16 expression was reduced in clinical tumor tissues. In vitro experiments revealed that the proportion of 7-AAD + NK-92 cells cocultured with GC cells was significantly increased, accompanied by increased cell mortality and decreased IFN- and TNF- secretion. Further studies revealed that circPDSS1 expression was abnormally elevated in GC tissues and cells and was particularly enriched in MKN-45 cell-derived exosomes (Exos). Knockdown of circPDSS1 alleviated MKN-45-Exo-induced cell damage; reduced lipid ROS, MDA, and Fe 2+ levels in NK-92 cells; and delayed tumor progression. Furthermore, a ferroptosis inhibitor suppressed circPDSS1 overexpression-induced cell death. Mechanistically, circPDSS1 sponged miR-142-3p to upregulate ACSL4 expression, promoting NK cell ferroptosis. Exosomal circPDSS1 derived from GC cells contributes to NK cell ferroptosis by sponging miR-142-3p to increase ACSL4 expression and exacerbate GC.
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