期刊
ONCOTARGET
卷 6, 期 36, 页码 39262-39275出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.5741
关键词
RELA; NFKB1; MMP1; PAR1; lymph endothelial cell migration
资金
- technology grant (TSA Doktorat) - Austria Federal Ministry of Science and Research (BMFW) Asea Uninet
- Fund of the Mayor of the City of Vienna [BGM 14049]
- Herzfelder Family Foundation
RELA, RELB, CREL, NFKB1 and NFKB2, and the upstream regulators NEMO and NIK were knocked-down in lymph endothelial cells (LECs) and in MDA-MB231 breast cancer spheroids to study the contribution of NF-kappa B in vascular barrier breaching. Suppression of RELA, NFKB1 and NEMO inhibited circular chemo-repellent induced defects (CCIDs), which form when cancer cells cross the lymphatic vasculature, by similar to 20-30%. Suppression of RELB, NFKB2 and NIK inhibited CCIDs by only similar to 10-15%. In MDA-MB231 cells RELA and NFKB1 constituted MMP1 expression, which caused the activation of PAR1 in adjacent LECs. The knock-down of MMP1 in MDA-MB231 spheroids and pharmacological inhibition of PAR1 in LECs inhibited CCID formation by similar to 30%. Intracellular Ca2+ release in LECs, which was induced by recombinant MMP1, was suppressed by the PAR1 inhibitor SCH79797, thereby confirming a functional intercellular axis: RELA/NFKB1 - MMP1 (MDA-MB231) - PAR1 (LEC). Recombinant MMP1 induced PAR1-dependent phosphorylation of MLC2 and FAK in LECs, which is indicative for their activity and for directional cell migration such as observed during CCID formation. The combined knock-down of the NF-kappa B pathways in LECs and MDA-MB231 spheroids inhibited CCIDs significantly stronger than knock-down in either cell type alone. Also the knock-down of ICAM-1 in LECs (a NF-kappa B endpoint with relevance for CCID formation) and knock-down of MMP1 in MDA-MB231 augmented CCID inhibition. This evidences that in both cell types NF-kappa B significantly and independently contributes to tumour-mediated breaching of the lymphatic barrier. Hence, inflamed tumour tissue and/or vasculature pose an additional threat to cancer progression.
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