RESUMO
Leucine-rich α2-glycoprotein-1 (LRG1) is overexpressed in various cancers, including non-small cell lung cancer (NSCLC), but its role in NSCLC cell metastasis is not well understood. In this study, NSCLC cell exosomes were analyzed using different techniques, and the impact of exosomal LRG1 on NSCLC cell behavior was investigated through various assays both in vitro and in vivo. The study revealed that LRG1, found abundantly in NSCLC cells and exosomes, enhanced cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT). Exosomal LRG1 was shown to promote NSCLC cell metastasis in animal models. Additionally, the interaction between LRG1 and fibronectin 1 (FN1) in the cytoplasm was identified. It was observed that FN1 could counteract the effects of LRG1 knockdown on cell regulation induced by exosomes derived from NSCLC cells. Overall, the findings suggest that targeting exosomal LRG1 or FN1 may hold therapeutic potential for treating NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Movimento Celular , Proliferação de Células , Exossomos , Fibronectinas , Glicoproteínas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Humanos , Exossomos/metabolismo , Exossomos/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/genética , Proliferação de Células/genética , Fibronectinas/metabolismo , Fibronectinas/genética , Animais , Glicoproteínas/metabolismo , Glicoproteínas/genética , Movimento Celular/genética , Camundongos , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/genética , Camundongos Nus , Metástase Neoplásica , Camundongos Endogâmicos BALB C , Regulação Neoplásica da Expressão Gênica , Células A549RESUMO
Immune evasion is one of the critical hallmarks of malignant tumors, especially non-small cell lung cancer (NSCLC). Emerging findings have illustrated the roles of N6-methyladenosine (m6A) on NSCLC immune evasion. Here, this study investigated the function and underlying mechanism of m6A reader YTH domain family protein 3 (YTHDF3) on NSCLC immune evasion. YTHDF3 was found to be highly expressed in NSCLC tissue and act as an independent prognostic factor for overall survival. Functionally, up-regulation of YTHDF3 impaired the CD8+ T antitumor activity to deteriorate NSCLC immune evasion, while YTHDF3 silencing recovered the CD8+ T antitumor activity to inhibit immune evasion. Besides, YTHDF3 up-regulation reduced the apoptosis of NSCLC cells. Mechanistically, PD-L1 acted as the downstream target for YTHDF3, and YTHDF3 could upregulate the transcription stability of PD-L1 mRNA. Overall, YTHDF3 targeted PD-L1 to promote NSCLC immune evasion partially through escaping effector cell cytotoxicity CD8+ T mediated killing and antitumor immunity. In summary, this study provides an essential insight for m6A modification on CD8+ T cell-mediated antitumor immunity in NSCLC, which might inspire an innovation for lung cancer tumor immunotherapy.