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.
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.
['Lin|Xian|X|', 'Lin|Bing-Wen|BW|', 'Chen|Xiao-Li|XL|', 'Zhang|Bei-Lei|BL|', 'Xiao|Xiong-Jian|XJ|', 'Shi|Jing-Shi|JS|', 'Lin|Jian-Dong|JD|', 'Chen|Xiao|X|']
D000818:Animals D014408:Biomarkers, Tumor D002289:Carcinoma, Non-Small-Cell Lung D045744:Cell Line, Tumor D058750:Epithelial-Mesenchymal Transition D025461:Feedback, Physiological D055785:Gene Knockdown Techniques D064593:Heterografts D006801:Humans D008175:Lung Neoplasms D008297:Male D051379:Mice D008819:Mice, Nude D035683:MicroRNAs D018832:Molecular Chaperones D017395:Plasminogen Activator Inhibitor 1 D011379:Prognosis D050828:Protein Inhibitors of Activated STAT D050796:STAT3 Transcription Factor D015398:Signal Transduction
PAI-1 Stat3 miR-34a Metastasis NSCLC microRNAs