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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- 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).