TRAIL Regulate CXCR4 Expression And To Study The Molecular Mechanism Of Tumor Metastasis Suppression

Migration and invasion are important character of cancer cells，and lethal cause ofpatients in clinic. But the mechanism is not clear even though the molecular biology havebeen developed for several decades. Cancer cells migrate to other tissues via lymph nodeor vessel often with organ specificity. Cancer cells usually invade to other tissues viachemokine receptor CXCL12/CXCR4axis，which is highly correlated with tumormetastasis.Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which is alsodesignated as Apo-2ligand (Apo2L)，is a typical member of the structurally related TNFfamily. TRAIL has been known to induce apoptosis specifically in a vairety of tumorcells，but not in most normal cells. Thus, TRAIL and TRAIL death receptor (DR4，DR5)specific agonistic antibodies have attracted considerable attention for their potential usein cancer therapy. There are more and more data demonstrating that TRAIL plays animportant role in both innate and adaptive immunity.MDA-MB-231is a breast cancer cell line，which could be induced to apoptosis byTRAIL at a low dosage. In the present study, we found that TRAIL not only inducedMDA-MB-231cell apoptosis，but also decreased chemokine receptor CXCR4expression.CXCR4，a chemotactic factor receptor, is one member of the GPCR (G-protein coupledreceptors) superfamily. CXCR4actives intracellular signal transduction upon bindingwith its ligand SDF-la，therefore, involves in a series of physiological effects includingchemotaxis, proliferation, metabolism, regulation, immune regulation, and etc. In thepresent study, we found that CXCR4was a key factor in MDA-MB-231cell migration.CXCR4affected cell migration along with its expression level changed. TRAIL activedNF-kB activity and then upregulated mir-146a expression which targeted on CXCR4gene and repressed CXCR4expression. Knockdown CXCR4expression with siRNA orover expression of mir-146a suppressed MDMB-231cell migration significantly. Furthermore, TRAIL upregulated mir-146a expression and decreased CXCR4expressionin tumor xenogratf animal model.In summary, TRAIL upregulates mir-146a expression，therefore suppresses its targetgene CXCR4expression, and then decreases breast cancer cell migration. These dataprovide a novel implication in breast cancer therapy by using TRAIL and relatedtherapeutics..