Department of Oncology, Xuzhou City Cancer Hospital, Xuzhou Third People's Hospital, Xuzhou Hospital Affiliated to Jiangsu University, No. 131 Huancheng Road, Gulou District, Xuzhou, 221000, People's Republic of China.
Jiangsu University, Zhenjiang, 212013, People's Republic of China.
J Transl Med. 2023 Apr 1;21(1):238. doi: 10.1186/s12967-023-04055-0.
Extracellular vesicles (EVs) transport biologically active molecules, and represent a recently identified way of intercellular communication. Recent evidence has also reported that EVs shed by cancer stem cells (CSCs) make a significant contribution to carcinogenesis and metastasis. Here, this study aims to explore the possible molecular mechanism of CSCs-EVs in gastric cancer (GC) by mediating intratumor communication network.
CSCs and non-stem cancer cells (NSCCs) were sorted from GC cells, and EVs were isolated from CSCs. H19 was knocked down in CSCs, and CSCs-EVs or CSCs-EVs containing shRNA-H19 (CSCs-EVs-sh-H19) were co-cultured with NSCCs, followed by evaluation of the malignant behaviors and stemness of NSCCs. Mouse models of GC were established and injected with CSCs-EVs from sh-H19-treated NSCCs in vivo.
CSCs had notable self-renewal and tumorigenic capacity compared with NSCCs. CSCs promoted the malignant behaviors of NSCCs and expression of stemness marker proteins through secretion of EVs. Inhibited secretion of CSCs-EVs curtailed the tumorigenicity and metastasis of NSCCs in vivo. H19 could be delivered by CSCs-EVs into NSCCs. H19 promoted the malignant behaviors of NSCCs and stemness marker protein expression in vitro along with tumorigenicity and liver metastasis in vivo, which was mechanistically associated with activation of the YAP/CDX2 signaling axis.
Taken together, the present study points to the importance of a novel regulatory axis H19/YAP/CDX2 in carcinogenic and metastatic potential of CSCs-EVs in GC, which may be potential targets for anticancer therapy.
细胞外囊泡（EVs）运输具有生物活性的分子，是最近发现的一种细胞间通讯方式。最近的证据还表明，肿瘤干细胞（CSCs）释放的 EVs 对癌发生和转移有重要贡献。在这里，本研究旨在通过调节肿瘤内通讯网络来探索 CSCs-EVs 在胃癌（GC）中的可能分子机制。
从 GC 细胞中分离 CSCs 和非干细胞癌细胞（NSCCs），并从 CSCs 中分离 EVs。在 CSCs 中敲低 H19，将 CSCs-EVs 或含有 shRNA-H19 的 CSCs-EVs（CSCs-EVs-sh-H19）与 NSCCs 共培养，然后评估 NSCCs 的恶性行为和干细胞特性。在体内建立 GC 小鼠模型，并注射来自 sh-H19 处理的 NSCCs 的 CSCs-EVs。
与 NSCCs 相比，CSCs 具有明显的自我更新和致瘤能力。CSCs 通过分泌 EVs 促进 NSCCs 的恶性行为和干细胞标记蛋白的表达。抑制 CSCs-EVs 的分泌可减少 NSCCs 在体内的致瘤性和转移。H19 可以通过 CSCs-EVs 递送到 NSCCs 中。H19 在体外促进 NSCCs 的恶性行为和干细胞标记蛋白的表达以及体内的致瘤性和肝转移，其机制与 YAP/CDX2 信号轴的激活有关。
综上所述，本研究指出了 H19/YAP/CDX2 这一新型调控轴在 GC 中 CSCs-EVs 的致癌和转移潜能中的重要性，这可能是癌症治疗的潜在靶点。
