Exosomal long noncoding RNA MLETA1 promotes tumor progression and metastasis by regulating the miR-186-5p/EGFR and miR-497-5p/IGF1R axes in non-small cell lung cancer

Journal of Experimental & Clinical Cancer Research

Research

Yi-Ying Wu¹  Ya-Ju Wu²  Ming-Shiu Lin³  Pan-Chyr Yang⁴  Jia-En Wu⁵  Chia-Hao Tung⁵  Xiu-Rui Hsu⁵  Meng-Fan Huang⁵  Tse-Ming Hong⁶  Sheng-Yen Hsiao⁷  Jui-Lin Liang⁸  Yuh-Ling Chen⁹ 

[1] Clinical Medicine Research Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan;Department of Pathology, Chi Mei Medical Center, Liouying, Tainan, Taiwan;Institute of Biomedical Sciences, Academia Sinica, 115, Taipei, Taiwan;Institute of Biomedical Sciences, Academia Sinica, 115, Taipei, Taiwan;Department of Internal Medicine, College of Medicine, National Taiwan University, 100, Taipei, Taiwan;YongLin Institute of Health, National Taiwan University, Taipei, Taiwan;Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan;Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan;Clinical Medicine Research Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan;Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan;Department of Internal Medicine, Division of Hematology-Oncology, Chi Mei Medical Center, Liouying, Tainan, Taiwan;Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan;Department of Surgery, Chi-Mei Medical Center, Liouying, Tainan, Taiwan;Institute of Oral Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan;

关键词: Lnc-MLETA1;    Lung cancer metastasis;    Exosome;    miR-186-5p;    miR-497-5p;    IGF1R;    EGFR;   

DOI  :  10.1186/s13046-023-02859-y

 received in 2023-06-02, accepted in 2023-10-10,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundLung cancer is the most common and deadliest cancer worldwide, and approximately 90% of all lung cancer deaths are caused by tumor metastasis. Tumor-derived exosomes could potentially promote tumor metastasis through the delivery of metastasis-related molecules. However, the function and underlying mechanism of exosomal long noncoding RNA (lncRNA) in lung cancer metastasis remain largely unclear.MethodsCell exosomes were purified from conditioned media by differential ultracentrifugation and observed using transmission electron microscopy, and the size distributions were determined by nanoparticle tracking analysis. Exosomal lncRNA sequencing (lncRNA-seq) was used to identify long noncoding RNAs. Cell migration and invasion were determined by wound-healing assays, two-chamber transwell invasion assays and cell mobility tracking. Mice orthotopically and subcutaneously xenografted with human cancer cells were used to evaluate tumor metastasis in vivo. Western blot, qRT‒PCR, RNA-seq, and dual-luciferase reporter assays were performed to investigate the potential mechanism. The level of exosomal lncRNA in plasma was examined by qRT‒PCR. MS2-tagged RNA affinity purification (MS2-TRAP) assays were performed to verify lncRNA-bound miRNAs.ResultsExosomes derived from highly metastatic lung cancer cells promoted the migration and invasion of lung cancer cells with low metastatic potential. Using lncRNA-seq, we found that a novel lncRNA, lnc-MLETA1, was upregulated in highly metastatic cells and their secreted exosomes. Overexpression of lnc-MLETA1 augmented cell migration and invasion of lung cancer. Conversely, knockdown of lnc-MLETA1 attenuated the motility and metastasis of lung cancer cells. Interestingly, exosome-transmitted lnc-MLETA1 promoted cell motility and metastasis of lung cancer. Reciprocally, targeting lnc-MLETA1 with an LNA suppressed exosome-induced lung cancer cell motility. Mechanistically, lnc-MLETA1 regulated the expression of EGFR and IGF1R by sponging miR-186-5p and miR-497-5p to facilitate cell motility. The clinical datasets revealed that lnc-MLETA1 is upregulated in tumor tissues and predicts survival in lung cancer patients. Importantly, the levels of exosomal lnc-MLETA1 in plasma were positively correlated with metastasis in lung cancer patients.ConclusionsThis study identifies lnc-MLETA1 as a critical exosomal lncRNA that mediates crosstalk in lung cancer cells to promote cancer metastasis and may serve as a prognostic biomarker and potential therapeutic target for lung cancer diagnosis and treatment.

【 授权许可】

CC BY   
© Italian National Cancer Institute ‘Regina Elena’ 2023

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