Cancer stem cells (CSCs) are cancer‐initiating cells that are not only a source of tumorigenesis but also the cause of tumour progression, metastasis and therapy resistance. EBV‐associated gastric cancer (EBVaGC) is a distinct subtype of gastric cancer with unique clinicopathological and molecular features. However, whether CSCs exist in EBVaGC, and the tumorigenic mechanism of EBV, remains unclear. Here, NOD/SCID mice were injected subcutaneously with the EBVaGC cell line SNU719 and treated with 5‐fluorouracil weekly. Successive generations of xenografts yielded a highly malignant EBVaGC cell line, SNU‐4th, which displays properties of CSCs and mainly consists of CD44⁺CD24⁻ cells. In SNU‐4th cells, an EBV‐encoded circRNA, ebv‐circLMP2A, expression increased and plays crucial roles in inducing and maintaining stemness phenotypes through targeting miR‐3908/TRIM59/p53 axis. Additionally, high expression of ebv‐circLMP2A is significantly associated with metastasis and poor prognosis in patients with EBVaGC. These findings not only provide evidence for the existence of CSCs in EBVaGC and elucidate the pathogenic mechanism of ebv‐circLMP2A in EBVaGC, but also provide a promising therapeutic target for EBVaGC.

中文翻译：

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Epstein-Barr 病毒衍生的环状 RNA LMP2A 在 EBV 相关胃癌中诱导干性。

癌症干细胞（CSCs）是癌症起始细胞，不仅是肿瘤发生的来源，也是肿瘤进展、转移和治疗抵抗的原因。EBV相关胃癌（EBVaGC）是胃癌的一种独特亚型，具有独特的临床病理学和分子特征。然而，EBVaGC中是否存在CSC，以及EBV的致瘤机制仍不清楚。在这里，NOD/SCID 小鼠被皮下注射 EBVaGC 细胞系 SNU719，并每周用 5-氟尿嘧啶治疗。连续几代异种移植物产生了高度恶性的EBVaGC细胞系SNU-4th，它表现出CSC的特性，主要由CD44 ⁺ CD24 ^-细胞。在 SNU-4th 细胞中，EBV 编码的 circRNA ebv-circLMP2A 表达增加，并通过靶向 miR-3908/TRIM59/p53 轴在诱导和维持干性表型中发挥关键作用。此外，ebv-circLMP2A 的高表达与 EBVaGC 患者的转移和预后不良显着相关。这些发现不仅为EBVaGC中存在CSCs提供了证据，阐明了ebv-circLMP2A在EBVaGC中的致病机制，也为EBVaGC提供了一个有希望的治疗靶点。