1. PAI-1/PIAS3/Stat3/miR-34a forms a positive feedback loop to promote EMT-mediated metastasis through Stat3 signaling in Non-small cell lung cancer.
- Author
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Lin X, Lin BW, Chen XL, Zhang BL, Xiao XJ, Shi JS, Lin JD, and Chen X
- Subjects
- Animals, Biomarkers, Tumor metabolism, Carcinoma, Non-Small-Cell Lung genetics, Cell Line, Tumor, Epithelial-Mesenchymal Transition genetics, Epithelial-Mesenchymal Transition physiology, Feedback, Physiological, Gene Knockdown Techniques, Heterografts, Humans, Lung Neoplasms genetics, Lung Neoplasms pathology, Male, Mice, Mice, Nude, MicroRNAs genetics, Molecular Chaperones genetics, Plasminogen Activator Inhibitor 1 genetics, Prognosis, Protein Inhibitors of Activated STAT genetics, STAT3 Transcription Factor genetics, Signal Transduction, Carcinoma, Non-Small-Cell Lung metabolism, Carcinoma, Non-Small-Cell Lung secondary, Lung Neoplasms metabolism, MicroRNAs metabolism, Molecular Chaperones metabolism, Plasminogen Activator Inhibitor 1 metabolism, Protein Inhibitors of Activated STAT metabolism, STAT3 Transcription Factor metabolism
- Abstract
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., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
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