State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun 130062, China.
Int J Mol Sci. 2024 Sep 26;25(19):10350. doi: 10.3390/ijms251910350.
The human phosphatase and tensin homolog (PTEN) is a tumor suppressor. A slight deficiency in PTEN might cause cancer susceptibility and progression. Infection by the liver fluke could lead to persistent loss of PTEN in cholangiocarcinoma. However, the mechanism of PTEN loss and its malignant effect on cholangiocarcinoma have not yet been elucidated. Extracellular vesicles secreted by (CS-EVs) are rich in microRNAs (miRNAs) and can mediate communication between hosts and parasites. Herein, we delved into the miRNAs present in CS-EVs, specifically those that potentially target PTEN and modulate the progression of cholangiocarcinoma via ferroptosis mechanisms. CS-EVs were extracted by differential ultra-centrifugation for high-throughput sequencing of miRNA. Lentiviral vectors were used to construct stably transfected cell lines. Erastin was used to construct ferroptosis induction models. Finally, 36 miRNAs were identified from CS-EVs. Among them, csi-miR-96-5p inhibited PTEN expression according to the predictions and dual luciferase assay. The CCK-8 assay, xenograft tumor assays and transwell assay showed that csi-miR-96-5p overexpression and PTEN knockout significantly increased the proliferation and migration of cholangiocarcinoma cells and co-transfection of PTEN significantly reversed the effect. In the presence of erastin, the cell proliferation and migration ability of the negative transfection control group were significantly impaired, although they did not significantly change with transfection of csi-miR-96-5p and PTEN knockout, indicating that they obtained ferroptosis resistance. Mechanistically, csi-miR-96-5p and PTEN knockout significantly inhibited ferroptosis through a decrease in ferrous ion (Fe) and malondialdehyde (MDA), and an increase in glutathione reductase (GSH), Solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4). In conclusion, loss of PTEN promoted the progression of cholangiocarcinoma via the ferroptosis pathway and csi-miR-96-5p delivered by CS-EVs may mediate this process.
人类磷酸酶和张力蛋白同系物（PTEN）是一种肿瘤抑制因子。PTEN 的轻微缺陷可能导致癌症易感性和进展。肝吸虫感染可能导致胆管癌中持续丧失 PTEN。然而，PTEN 丧失的机制及其对胆管癌的恶性影响尚未阐明。 由 （CS-EVs）分泌的细胞外囊泡富含 microRNAs（miRNAs），可以介导宿主与寄生虫之间的通讯。在此，我们深入研究了 CS-EVs 中的 miRNAs，特别是那些可能靶向 PTEN 并通过铁死亡机制调节胆管癌进展的 miRNAs。通过差速超速离心法提取 CS-EVs 进行 miRNA 高通量测序。使用慢病毒载体构建稳定转染细胞系。使用 Erastin 构建铁死亡诱导模型。最后，从 CS-EVs 中鉴定出 36 个 miRNAs。其中，csi-miR-96-5p 根据预测和双荧光素酶测定抑制 PTEN 表达。CCK-8 测定、异种移植肿瘤测定和 Transwell 测定表明，csi-miR-96-5p 过表达和 PTEN 敲除显着增加胆管癌细胞的增殖和迁移，而共转染 PTEN 显着逆转了这种作用。在 Erastin 存在的情况下，阴性转染对照组的细胞增殖和迁移能力显着受损，尽管它们与 csi-miR-96-5p 转染和 PTEN 敲除没有显着变化，表明它们获得了铁死亡抗性。从机制上讲，csi-miR-96-5p 和 PTEN 敲除通过减少亚铁离子（Fe）和丙二醛（MDA），增加谷胱甘肽还原酶（GSH）、溶质载体家族 7 成员 11（SLC7A11）和谷胱甘肽过氧化物酶 4（GPX4）显着抑制铁死亡。总之，PTEN 的丧失通过铁死亡途径促进胆管癌的进展，CS-EVs 递送的 csi-miR-96-5p 可能介导这一过程。
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