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

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

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

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.

Original languageEnglish
Article number121945
JournalLife Sciences
Volume329
DOIs
Publication statusPublished - Sept 15 2023

Keywords

  • Brain metastasis
  • Cancer stem cell niche
  • DGKB/ERK/STAT3 signaling
  • ERK inhibitor
  • Extracellular vesicles (EVs)
  • Lung cancer
  • OncomiR miR-21

ASJC Scopus subject areas

  • General Biochemistry,Genetics and Molecular Biology
  • Pharmacology, Toxicology and Pharmaceutics(all)

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