title: The CCL2/CCR2 axis enhances IL-6-induced epithelial-mesenchymal transition by cooperatively activating STAT3-Twist signaling.
abstract: The pattern of secreted factors in the tumor microenvironment has been shown to initiate tumor epithelial-mesenchymal transition (EMT); however, little is known about their interplay undergoing this phenotypic switch. In this study, we revealed obvious coactions of cytokine IL-6 and chemokine CCL2 during EMT induction. We found that IL-6 effectively induced EMT and promoted tumor cell invasion, which could be markedly enhanced by addition of CCL2 in a CCR2-dependent manner. IL-6 and CCL2 induced each other and cooperatively elicited STAT3 phosphorylation; conversely, STAT3 regulated the production of IL-6 and CCL2, thus constituting a positive feedback loop to maintain and amplify STAT3 signaling, consequently promoting additional EMT events. Furthermore, CCL2 greatly enhanced IL-6-induced EMT events mainly by upregulating the expression of Twist. Genetic or pharmacological inhibition of STAT3 disrupted STAT3-centered loop and markedly suppressed Twist expression as well as IL-6/CCL2-mediated EMT induction. Thus, our findings highlighted the synergy of the two secreted factors of tumor microenvironment, in regulating transformed properties of non-small cell lung cancer (NSCLC).
authors.affiliation: Department of Respiratory, Navy General Hospital, Beijing, 100048, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Qiang
authors.initials: Q
authors.lastname: Gao
authors.forename: Siqi
authors.initials: S
authors.lastname: Han
authors.forename: Fei
authors.initials: F
authors.lastname: Pan
authors.forename: Wei
authors.initials: W
authors.lastname: Fan
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000235:genetics* / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000096:biosynthesis*; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000096:biosynthesis*; D015398:Signal Transduction; D059016:Tumor Microenvironment; D051879:Twist-Related Protein 1 / Q000096:biosynthesis*
chemical_list: D018932:Chemokine CCL2; C508600:IL6 protein, human; D015850:Interleukin-6; D009687:Nuclear Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1