5054

SERPINE1

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.CI - Copyright (c) 2017 Elsevier Inc. All rights reserved.

epithelial-mesenchymal transition (EMT) is a key developmental program in which epithelial cells lose polarity and become mesenchymal cells, and that is often activated during cancer invasion and metastasis. Triple negative breast cancer (TNBC) patients have a relatively aggressive biological behavior with a high risk of distant recurrence and metastasis. Here, we stimulated TNBC cells to undergo EMT, and detected the protein expression profiles of the protein secretion. High-throughput data showed that EMT could promote TNBC cells to secret PAI-1. We found that TNBC-secreted PAI-1 could increase cell growth, migration and invasion, and the expression of EMT markers in the TNBC cell lines and xenograft PAI-1-/- mice model. Using a tissues microarray of 165 TNBC patients and published breast cancer database, we found PAI-1 expression was significantly elevated in the breast cancer tissues, comparing with the normal adjacent tissues and was associated with prognosis of patients with TNBC. Taken together, our results suggests an important role of PAI-1 in the EMT process of TNBC cells and illustrates the great potential of developing PAI-1-targeting therapy for clinical TNBC patients.CI - Copyright (c) 2018 Elsevier B.V. All rights reserved.