Exosomal miR-21 determines lung-to-brain metastasis specificity through the DGKB/ERK axis within the tumor microenvironment.

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.

• Authors: Tung-Yu Tiong, Mei-Lin Chan, Chun-Hua Wang, Vijesh Kumar Yadav, Narpati Wesa Pikatan, Iat-Hang Fong, Chi-Tai Yeh, Kuang-Tai Kuo, Wen-Chien Huang
• Journal: Life sciences (Life Sci) Vol. 329 Pg. 121945 (Sep 15 2023) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 37454756 (Publication Type: Journal Article)
• Copyright: Copyright © 2023 Elsevier Inc. All rights reserved.

Chemical References

• MicroRNAs
• ulixertinib
• MIRN-21 microRNA, mouse

Topics

• Animals
• Mice
• Brain Neoplasms (genetics)
• Lung (metabolism)
• Lung Neoplasms (pathology)
• MicroRNAs (genetics, metabolism)
• Quality of Life
• Tumor Microenvironment