Journal
YONSEI MEDICAL JOURNAL
Volume 63, Issue 3, Pages 229-240Publisher
YONSEI UNIV COLL MEDICINE
DOI: 10.3349/ymj.2022.63.3.229
Keywords
Key Words; Small-cell lung cancer; cancer-associated fibroblasts; exosomes; MEG3; chemoresistance
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This study found that CAF-derived exosomes containing MEG3 lncRNA promote DDP chemoresistance in SCLC through regulation of the miR-15a5p/CCNE1 axis. These findings offer new insights for SCLC therapy.
Purpose: Long non-coding RNAs (lncRNAs) may act as oncogenes in small-cell lung cancer (SCLC). Exosomes containing lncRNAs released from cancer-associated fibroblasts (CAF) accelerate tumorigenesis and confer chemoresistance. This study aimed to explore the action mechanism of the CAF-derived lncRNA maternally expressed gene 3 (MEG3) on cisplatin (DDP) chemoresistance and cell processes in SCLC. Materials and Methods: Quantitative real-time PCR was conducted to determine the expression levels of MEG3, miR-15a-5p, and CCNE1. Cell viability and metastasis were measured by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-h-tetrazolium bromide and invasion assays, respectively. A xenograft tumor model was developed to confirm the effect of MEG3 overexpression on SCLC progression in vivo. Relationships between miR-15a-5p and MEG3/CCNE1 were predicted using StarBase software and validated by dual luciferase reporter assay. Western blotting was used to determine protein levels. A co-culture model was established to explore the effects of exosomes on MEG3 expression in SCLC cell lines. Results: MEG3 was overexpressed in SCLC tissues and cells. MEG3 silencing significantly repressed cell viability and metastasis in SCLC. High expression of MEG3 was observed in CAF-derived conditioned medium (CM) and exosomes, and promoted chemoresistance and cancer progression. Additionally, MEG3 was found to serve as a sponge of miR-15a-5p to mediate CCNE1 expression. Overexpression of miR-15a-5p and knockout of CCNE1 reversed the effects of MEG3 overexpression on cell viability and metastasis. Conclusion: MEG3 lncRNA released from CAF-derived exosomes promotes DDP chemoresistance via regulation of a miR-15a5p/CCNE1 axis. These findings may provide insight into SCLC therapy.
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