Tiong, Tung-Yu and Chan, Mei-lin and Wang, Chun-Hua and Yadav, Vijesh Kumar and Pikatan, Narpati Wesa and Fong, Iat-Hang and Yeh, Chi-Tai and Kuo, Kuang-Tai and Huang, Wen-Chien (2023) Exosomal miR-21 determines lung-to-brain metastasis specificity through the DGKB/ERK axis within the tumor microenvironment. Life Sciences, 329. ISSN 00243205
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Abstract
Background: Brain metastasis affects 20–40 of lung cancer patients, severely diminishing their quality of life. This research focuses on miR-21, overexpressed in these patients and inversely associated with DGKB in the ERK/STAT3 pathway, suggesting a dysregulated pathway with therapeutic potential. Aims: The objective was to investigate miR-21's role in lung cancer patients with brain metastases and whether targeting this pathway could improve treatment outcomes. We also examined the miR-21 content in tumor spheres-derived extracellular vesicles (EVs) and their influence on ERK/STAT3 signaling and metastasis. Materials and methods: Tumor spheres were created from metastatic lung cancer cells. We studied miR-21 levels in these spheres, their impact on macrophage polarization, and the transition of nonmetastatic lung cancer cells. Furthermore, we analyzed miR-21 content in EVs derived from these spheres and their effect on ERK/STAT3 signaling and metastasis potential. Key findings: We found tumor spheres had high miR-21 levels, promoting macrophage polarization and, epithelial–mesenchymal transition. These spheres-derived EVs, enriched with miR-21, accelerated ERK/STAT3 signaling and metastasis. Silencing miR-21 and inhibiting ERK signaling with ulixertinib notably mitigated these effects. Moreover, ulixertinib reduced brain metastasis incidence and increased survival in a mouse model and led to reduced tumor sphere generation and miR-21 levels in EVs. Significance: Our study highlights the exacerbation of lung-to-brain metastasis via miR-21-rich EV secretion. This underlines the therapeutic promise of targeting the miR-21/ERK/STAT3 pathway with ulixertinib for managing brain metastasis from lung cancer. © 2023 Elsevier Inc.
Item Type: | Article |
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Additional Information: | Cited by: 6 |
Uncontrolled Keywords: | DGKB protein; diacylglycerol kinase; microRNA; miR 21; mitogen activated protein kinase; STAT3 protein; ulixertinib; unclassified drug; adult; animal experiment; animal model; animal tissue; Article; brain metastasis; clinical article; controlled study; drug targeting; enzyme inhibition; epithelial mesenchymal transition; exosome; female; gene expression; gene silencing; human; human cell; lung cancer; macrophage; male; mouse; non small cell lung cancer; nonhuman; polarization; signal transduction; survival; tumor microenvironment; tumor spheroid |
Subjects: | R Medicine > R Medicine (General) |
Divisions: | Faculty of Medicine, Public Health and Nursing > Biomedical Sciences |
Depositing User: | Sri JUNANDI |
Date Deposited: | 31 Oct 2024 02:36 |
Last Modified: | 31 Oct 2024 02:36 |
URI: | https://ir.lib.ugm.ac.id/id/eprint/6050 |