RESUMEN
AIM: This study intented to clarify the intracellular effect of PAI-1 on Non-small cell lung cancer (NSCLC) metastasis and the precise mechanism involved. METHODS: The metastatic properties of NSCLC cells were determined by transwell assays and wound-healing assay in vitro. The mRNA and protein expressions of genes were analyzed by Real-time qPCR and western blot, respectively. Pulmonary metastasis model of NSCLC cells was established to evaluate the pro-metastasis effect of PAI-1 and anti-metastatic effect of miR-34a in vivo. The gene targets of miR-34a were confirmed by luciferase reporter assays. Chromatin immunoprecipitation assay was employed to detect the transcriptional regulation of miR-34a. Co-immunoprecipitation assay was performed to observe the interaction of proteins. RESULTS: PAI-1, which was elevated in NSCLC patients with recurrence and metastasis, augmented NSCLC metastasis and was negatively related to the prognosis of NSCLC. miR-34a, which was decreased in NSCLC patients with metastasis, attenuated NSCLC metastasis and was positively correlated with the prognosis of NSCLC. Moreover, PAI-1 was identified as the target gene of miR-34a and activated the Stat3 signaling pathway to promote epithelial-mesenchymal transition (EMT) in NSCLC cells. PAI-1 interacted with PIAS3 to regulate Stat3-dependent gene expression and miR-34a was transcriptionally suppressed by Stat3 to form a positive regulatory loop through Stat3 signaling. CONCLUSION: Our findings suggest that PAI-1 and miR-34a, which can be clinically utilized as biomarkers for the clinical prognosis or diagnosis of NSCLC, are potential targets for the treatment of NSCLC.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/secundario , Neoplasias Pulmonares/metabolismo , MicroARNs/metabolismo , Chaperonas Moleculares/metabolismo , Inhibidor 1 de Activador Plasminogénico/metabolismo , Proteínas Inhibidoras de STAT Activados/metabolismo , Factor de Transcripción STAT3/metabolismo , Animales , Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Línea Celular Tumoral , Transición Epitelial-Mesenquimal/genética , Transición Epitelial-Mesenquimal/fisiología , Retroalimentación Fisiológica , Técnicas de Silenciamiento del Gen , Xenoinjertos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratones Desnudos , MicroARNs/genética , Chaperonas Moleculares/genética , Inhibidor 1 de Activador Plasminogénico/genética , Pronóstico , Proteínas Inhibidoras de STAT Activados/genética , Factor de Transcripción STAT3/genética , Transducción de SeñalRESUMEN
BACKGROUND: Low levels of ascorbic acid (AA) have been detected in critically ill patients in which AA supplementation leads to promising outcomes. However, the ability of AA to reduce mortality in critically ill patients remains controversial. In this study, we have performed a meta-analysis to evaluate the effects of AA dose on the mortality of critically ill adults. METHODS: Electronic databases were searched for trials in which AA had been intravenously administered to critically ill patients regardless of the dose or the co-administration of antioxidant agents. The predefined primary outcome included all-cause mortality at final follow-up. RESULTS: The included trials enrolled a total of 1210 patients. Intravenous (IV) AA doses of 3-10 g/d reduced the mortality of critically ill patients (OR 0.25; 95% CI (0.14-0.46); p < 0.001; I2 = 0.0%), while low (< 3 g/d) and high AA doses (≥ 10 g/d) had no effect (OR 1.44; 95% CI (0.79-2.61); p = 0.234; I2 = 0.0% versus OR 1.12; 95% CI (0.62-2.03); p = 0.700; I2 = 0.0%). AA was associated with a decreased duration of vasopressor support and mechanical ventilation, but did not influence fluid requirement or urine output during the first 24 h of admission. The number of patients suffering from acute kidney injury and the length of intensive care unit or hospital stays were also unaffected by the AA. CONCLUSION: Intravenous AA reduces the duration of vasopressor support and mechanical ventilation; 3-10 g AA results in lower overall mortality rates. Given the limitations of the primary literature, further studies are required to fully clarify the effectiveness of AA during the management of critically ill patients.