The CCL2/CCR2 axis enhances IL-6-induced epithelial-mesenchymal transition by cooperatively activating STAT3-Twist signaling

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• 作者：Wei Chen (1)
  Qiang Gao (2)
  Siqi Han (3)
  Fei Pan (4)
  Wei Fan (5)
  
  1. Department of Respiratory ; Navy General Hospital ; Beijing ; 100048 ; China
  2. Department of Geriatrics ; Second Affiliated Hospital of Harbin Medical University ; Haerbin ; 150086 ; China
  3. Department of Medical Oncology ; Jinling Hospital ; Nanjing ; 210002 ; China
  4. Department of Gastroenterology and Hepatology ; Chinese PLA General Hospital ; Beijing ; 100853 ; China
  5. Department of Anesthesiology ; Huai鈥檃n First People鈥檚 Hospital ; Nanjing Medical University ; 6 Beijing Road West ; Huai鈥檃n ; 223300 ; China
  
• 关键词：IL ; 6 ; CCL2 ; Coaction ; Epithelial ; mesenchymal transition ; Tumor microenvironment ; Metastasis
• 刊名：Tumor Biology
• 出版年：2015
• 出版时间：February 2015
• 年：2015
• 卷：36
• 期：2
• 页码：973-981
• 全文大小：1,599 KB
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• 刊物主题：Cancer Research;
• 出版者：Springer Netherlands
• ISSN：1423-0380

文摘

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).