RESUMO
BACKGROUND: Exosomes are mediators of intercellular communication. Cancer cell-secreted exosomes allow exosome donor cells to promote cancer growth, as well as metastasis. METHODS: Here, exosomes were isolated from the serum of non-small cell lung cancer (NSCLC) patients and characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and western blot analysis. NSCLC cell proliferation and migration were assessed using CCK-8, 5-ethynyl-2'-deoxyuridine (EdU) and Transwell assays. H1299 tumor formation and pulmonary metastasis were examined in a xenograft model in nude mice. RESULTS: We found that exosomes derived from NSCLC (NSCLC-Exos) promoted NSCLC cell migration and proliferation, and that NSCLC-Exo-mediated malignant progression of NSCLC was mediated by miR-199b-5p. Inhibition of miR-199b-5p decreased the effects of NSCLC-Exos on NSCLC malignant progression. HIF1AN was identified as a downstream target of miR-199b-5p. Furthermore, overexpression of HIF1AN reversed the effects of miR-199b-5p on NSCLC malignant progression. CONCLUSION: In summary, our findings demonstrated that exosomal-specific miR-199b-5p promoted proliferation in distant or neighboring cells via the miR-199b-5p/HIF1AN axis, resulting in enhanced tumor growth.
RESUMO
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial pneumonia with limited therapeutic options. Eucalyptol, a terpenoid oxide isolated from eucalyptus species, reportedly exhibits various biological activities such as anti-inflammatory and antioxidant effects. In the present study, we aimed to determine whether eucalyptol could alleviate bleomycin (BLM)-induced pulmonary fibrosis and inhibit interleukin (IL)-13-induced M2 macrophage polarization. Upon treatment with eucalyptol, BLM-induced pulmonary fibrosis and lung inflammation were significantly reduced. The pulmonary neutrophil accumulation and pulmonary permeability were inhibited and the expression of hydroxyproline, alpha-smooth muscle actin, and fibronectin was significantly down-regulated. Eucalyptol also markedly inhibited the expression of arginase-1, Ym-1, IL-13, and transforming growth factor (TGF)-ß1, reduced the production of IL-13, IL-6, tumor necrosis factor (TNF)-α, and attenuated the activity of TGF-ß1 in bronchoalveolar lavage fluid (BALF). Furthermore, the in vitro assay revealed that eucalyptol disturbed M2 macrophage polarization and reduced the macrophage-mediated secretion of the profibrotic factor TGF-ß1. Eucalyptol inhibited the nuclear location of signal transducer and activator of transcription 6 (STAT6) and the phosphorylation of STAT6 and p38 mitogen-activated protein kinase (p38 MAPK), and reduced the expression of their downstream transcription factors, krupple-like factor 4 (KLF4) and peroxisome proliferator-activated receptor gamma (PPAR-γ). These findings indicated that eucalyptol alleviates BLM-induced pulmonary fibrosis by regulating M2 macrophage polarization, which, in turn, inhibits the activation of signaling molecules (e.g., STAT6 and p38 MAPK) and the expression of transcription factors (e.g., KLF4 and PPAR-γ). Thus, eucalyptol might be a potential therapeutic agent for IPF.
Assuntos
Bleomicina , Fibrose Pulmonar , Bleomicina/efeitos adversos , Eucaliptol/farmacologia , Eucaliptol/uso terapêutico , Humanos , Interleucina-13/metabolismo , Pulmão/patologia , Macrófagos/metabolismo , PPAR gama/metabolismo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/prevenção & controle , Fator de Crescimento Transformador beta1/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
OBJECTIVE: To investigate the correlation between melanoma antigen gene A3 (MAGE-A3) expression and progression-free survival (PFS) of nonsmall cell lung cancer (NSCLC) patients with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKIs) therapy, aiming to provide a basis for research and treatment of EGFR-TKIs resistance. RESEARCH AND METHODS: Retrospective analysis is conducted of PFS of 359 NSCLC patients who have been tested positive for EGFR, and experienced drug resistance during oral treatment of icotinib. MAGE-A3 expression is tested using immunology and histology chemistry methods, and T790M and c-MeT expression are tested using mutation-enriched polymerase chain reaction. RESULTS: (1) MAGE-A3 expression in targeted treatment of NSCLC patients shows a positive rate of 33.98%. The comparative difference between MAGE-A3 expression and T790M, c-MeT and other resistance genes was not statistically significant (P > 0.05). (2) MAGE-A3 expression was higher in patients with NSCLC targeted therapy of primary drug resistance of positive rate than acquired resistance; meanwhile the expression level differences in three modes of acquired resistance are statistically significant (P < 0.05). (3) PFS of MAGE-A3 positive expression in the targeted treatment of acquired drug resistance in patients with NSCLC is shorter than the PFS of MAGE-A3 negative expression (P = 0.01); the comparative PFS differences in the three kinds of acquired drug resistance pattern have statistical significance (P = 0.02). (4) PFS and levels of MAGE-A3 expression in NSCLC patients with the three modes of acquired resistance are negatively correlated (P < 0.01), and MAGE-A3 expression has no correlation with age, gender, pathological type or PS score (P > 0.05). CONCLUSION: MAGE-A3 expression in EGFR-TKIs target therapy in NSCLC patient suggests that there might be EGFR-TKIs drug resistance, and the higher the level of expression, the shorter the time of acquired drug resistance.