Background and Aims Despite the presence of neutrophil extracellular traps [NETs] in inflamed colon having been confirmed, the role of NETs, especially the circulating NETs, in the progression and thrombotic tendency of inflammatory bowel disease [IBD] remains elusive. We extended our previous study to prove that NETs constitute a central component in the progression and prothrombotic state of IBD. Methods In all 48 consecutive patients with IBD were studied. Acute colitis was induced by the treatment of C57BL/6 mice with 3.5% dextran sulphate sodium [DSS] in drinking water for 6 days. Peripheral blood neutrophils and sera were collected from IBD patients and murine colitis models. Exposed phosphatidylserine [PS] was analysed with flow cytometry and confocal microscopy. Procoagulant activity was evaluated using clotting time, purified coagulation complex, and fibrin formation assays. Results We observed higher plasma NET levels and presence of NETs in colon tissue in patients with active IBD. More importantly, NETs were induced in mice with DSS colitis, and inhibition of NET release attenuated colitis as well as colitis-associated tumorigenesis. NET degradation through DNase administration decreased cytokine levels during DSS-induced colitis. In addition, DNase treatment also significantly attenuated the accelerated thrombus formation and platelet activation observed in DSS-induced colitis. NETs triggered PS-positive microparticle release and PS exposure on platelets and endothelial cells partially through TLR2 and TLR4, converting them to a procoagulant phenotype. Conclusions NETs exacerbate colon tissue damage and drive thrombotic tendency during active IBD. Strategies directed against NET formation may offer a potential therapeutic approach for the treatment of IBD.

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Yes-associated protein 1 (YAP1) contributes to the development of multiple tumors, but the mechanism underlying YAP1 deregulation in non-small cell lung cancer (NSCLC) remains unclear. By performing immunohistochemistry (IHC) assays, we found that YAP1 was significantly upregulated in NSCLC compared with adjacent tissues; therefore, we sought to elucidate whether the upregulation of YAP1 contributes to NSCLC progression. MTT and transwell assays showed that YAP1 overexpression promoted proliferation, migration, and invasion in the NSCLC cell lines A549 and H460; YAP1 overexpression also promoted the significant differential expression of epithelial-mesenchymal transition (EMT)-related markers. Nevertheless, YAP1 knockdown alleviated TGF-β1-induced EMT and proliferation, migration, and invasion in NSCLC. Furthermore, western blotting showed that the co-transcription complex YAP1/TEAD was impaired by YAPS94A (a YAP1 mutant without the TEAD binding site), and verteporfin (a small molecular inhibitor of YAP1) inhibited A549 and H460 cell metastasis and EMT-related markers expression, indicating that TEAD mediated the NSCLC aggressiveness induced by YAP1. Moreover, sequence analysis and ChIP and luciferase assays confirmed that YAP1 transcriptionally activated Slug expression by binding to TEAD. Importantly, silencing YAP1 inhibited A549 cell tumorigenesis and EMT and downregulated Slug expression in vivo. Overall, our findings revealed that YAP1 is a driver of NSCLC metastasis because YAP1 promoted the EMT program by inducing Slug transcription.

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BackgroundA deeper mechanistic understanding of epithelial-to-mesenchymal transition (EMT) regulation is needed to improve current anti-metastasis strategies in ovarian cancer (OvCa). This study was designed to investigate the role of lncRNAs in EMT regulation during process of invasion-metastasis in serous OvCa to improve current anti-metastasis strategies for OvCa.MethodsWe systematically analyzes high-throughput gene expression profiles of both lncRNAs and protein-coding genes in OvCa samples with integrated epithelial (iE) subtype and integrated mesenchymal (iM) subtype labels. Mouse models, cytobiology, molecular biology assays and clinical samples were performed to elucidate the function and underlying mechanisms of lncRNA PTAF-mediated promotion of EMT and invasion-metastasis in serous OvCa.ResultsWe constructed a lncRNA-mediated competing endogenous RNA (ceRNA) regulatory network that affects the expression of many EMT-related protein-coding genes in mesenchymal OvCa. Using a combination of in vitro and in vivo studies, we provided evidence that the lncRNA PTAF-miR-25-SNAI2 axis controlled EMT in OvCa. Our results revealed that up-regulated PTAF induced elevated SNAI2 expression by competitively binding to miR-25, which in turn promoted OvCa cell EMT and invasion. Moreover, we found that silencing of PTAF inhibited tumor progression and metastasis in an orthotopic mouse model of OvCa. We then observed a significant correlation between PTAF expression and EMT markers in OvCa patients.ConclusionsThe lncRNA PTAF, a mediator of TGF-β signaling, can predispose OvCa patients to metastases and may serve as a potential target for anti-metastatic therapies for mesenchymal OvCa patients.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0844-7) contains supplementary material, which is available to authorized users.

Triple-negative breast cancer (TNBC) has a poorer outcome than other subtypes of breast cancer, and the discovery of dysregulated microRNA (miRNA) and their role in tumor progression has provided a new avenue for elucidating the mechanism involved in TNBC. In this study, we identified that miR-3178 was significantly reduced in TNBC, and the low miR-3178 expression correlated with poor overall survival in TNBC but not in non-TNBC. The ectopic overexpression of miR-3178 suppressed TNBC cell proliferation, invasion, and migration by inhibiting the epithelial-to-mesenchymal (EMT) transition. Notch1 was validated as the direct target gene of miR-3178, which was confirmed by the dual-luciferase reporter assay. miR-3178 decreased the expression of Notch1 and restoration of Notch1 expression attenuated the inhibitory effects of miR-3178 on cell proliferation, metastasis, and the EMT in TNBC. miR-3178 inhibited cell proliferation and metastasis by targeting Notch1 in TNBC, and the restoration of miR-3178 might be a potential therapeutic strategy for TNBC.

BackgroundDespite great advances in the treatment of breast cancer, innovative approaches are still needed to reduce metastasis. As a minimally invasive local therapy (not standard therapy for breast cancer), microwave ablation (MWA) has been attempted to treat breast cancer, but the local effect and immune response induced by MWA have seldom been reported.MethodsThe clinical study was performed to determine the complete ablation rate of MWA for early-stage breast cancer. Secondary endpoints included safety and antitumor immune response. 35 subjects from this clinical study were enrolled in the current report, and the local effect was determined by pathological examinations or follow-up. To investigate MWA-induced immune response, patients treated with surgery (n=13) were enrolled as control, and blood samples were collected before and after MWA or surgery. The immune cell populations, serum cytokines, secretory immune checkpoint molecules, and T-cell receptor sequencing were analyzed.ResultsOf 35 enrolled patients, 32 (91.4%) showed complete ablation. Compared with surgery, MWA induced significantly increased levels of inducible co-stimulator (ICOS)+ activated CD4+ T cells and serum interferon gamma, indicating a shift in the Th1/Th2 balance toward Th1. The activated ICOS pathway was involved in the MWA-induced adaptive immune response. T-cell receptor sequencing revealed MWA of primary tumor activated T lymphocytes expansion and recognized some cancer-specific antigens. Moreover, CD4+ effector memory T-cell response was induced by MWA, and the immune response still existed after surgical resection of the ablated tumor.ConclusionsMWA may not only be a promising local therapy but also a trigger of antitumor immunity for breast cancer, opening new avenues for the treatment of breast cancer. Combinatorial strategy using additional agents which boost MWA-induced immune response could be considered as potential treatment for clinical study for early breast cancer therapy.

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