Chen Wei, Gao Qiang, Han Siqi, Pan Fei, Fan Wei
Department of Respiratory, Navy General Hospital, Beijing, 100048, China.
Tumour Biol. 2015 Feb;36(2):973-81. doi: 10.1007/s13277-014-2717-z. Epub 2014 Oct 16.
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).
肿瘤微环境中分泌因子的模式已被证明可引发肿瘤上皮-间质转化（EMT）；然而，对于它们在这种表型转换过程中的相互作用却知之甚少。在本研究中，我们揭示了细胞因子IL-6和趋化因子CCL2在EMT诱导过程中的明显协同作用。我们发现IL-6有效诱导EMT并促进肿瘤细胞侵袭，加入CCL2后，其侵袭能力可通过CCR2依赖性方式显著增强。IL-6和CCL2相互诱导并协同引发STAT3磷酸化；相反，STAT3调节IL-6和CCL2的产生，从而构成一个正反馈环，以维持和放大STAT3信号，进而促进更多的EMT事件。此外，CCL2主要通过上调Twist的表达来极大地增强IL-6诱导的EMT事件。对STAT3进行基因或药理学抑制会破坏以STAT3为中心的环，并显著抑制Twist表达以及IL-6/CCL2介导的EMT诱导。因此，我们的研究结果突出了肿瘤微环境中两种分泌因子在调节非小细胞肺癌（NSCLC）转化特性方面的协同作用。
