Tumor Biology

, Volume 36, Issue 2, pp 973–981 | Cite as

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

  • Wei Chen
  • Qiang Gao
  • Siqi Han
  • Fei Pan
  • Wei FanEmail author
Research Article


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).


IL-6 CCL2 Coaction Epithelial-mesenchymal transition Tumor microenvironment Metastasis 


Conflicts of interest



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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Wei Chen
    • 1
  • Qiang Gao
    • 2
  • Siqi Han
    • 3
  • Fei Pan
    • 4
  • Wei Fan
    • 5
    Email author
  1. 1.Department of RespiratoryNavy General HospitalBeijingChina
  2. 2.Department of GeriatricsSecond Affiliated Hospital of Harbin Medical UniversityHaerbinChina
  3. 3.Department of Medical OncologyJinling HospitalNanjingChina
  4. 4.Department of Gastroenterology and HepatologyChinese PLA General HospitalBeijingChina
  5. 5.Department of Anesthesiology, Huai’an First People’s HospitalNanjing Medical UniversityHuai’anChina

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