Extracellular Vesicles from Cerebrospinal Fluid of Leptomeningeal Metastasis Patients Deliver MiR-21 and Induce Methotrexate Resistance in Lung Cancer Cells

Autor: Ji Hye Im, Kyue-Yim Lee, Yoona Seo, Jiho Rhim, Yun-Sik Dho, Byong Chul Yoo, Jong Bae Park, Sang Hoon Shin, Heon Yoo, Jong Heon Kim, Ho-Shin Gwak
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: International Journal of Molecular Sciences, Vol 25, Iss 6, p 3124 (2024)
Druh dokumentu: article
ISSN: 1422-0067
1661-6596
DOI: 10.3390/ijms25063124
Popis: Leptomeningeal metastasis (LM) is a common and fatal complication of advanced non-small cell lung cancer (NSCLC) caused by the spread of malignant cells to the leptomeninges and cerebrospinal fluid (CSF). While intra-CSF methotrexate (MTX) chemotherapy can improve prognosis, eventual MTX resistance deters continued chemotherapy. Recent studies have shown that increased miRNA-21 (miR-21) expression in the CSF of patients with LM after intraventricular MTX-chemotherapy is associated with poor overall survival; however, the molecular mechanisms underlying this resistance are poorly understood. Here, we confirm, in 36 patients with NSCLC-LM, that elevated miR-21 expression prior to treatment correlates with poor prognosis. MiR-21 overexpression or sponging results in a corresponding increase or decrease in MTX resistance, demonstrating that cellular miR-21 expression correlates with drug resistance. MiR-21-monitoring sensor and fluorescent extracellular vesicle (EV) staining revealed that EV-mediated delivery of miR-21 could modulate MTX resistance. Moreover, EVs isolated from the CSF of LM patients containing miR-21 could enhance the cell proliferation and MTX resistance of recipient cells. These results indicate that miR-21 can be transferred from cell-to-cell via EVs and potentially modulate MTX sensitivity, suggesting that miR-21 in CSF EVs may be a prognostic and therapeutic target for overcoming MTX resistance in patients with NSCLC-LM.
Databáze: Directory of Open Access Journals
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