Aberrantly expressed Fra-1 by IL-6/STAT3 transactivation promotes colorectal cancer aggressiveness through epithelial-mesenchymal transition
Aberrantly expressed Fra-1 by IL-6/STAT3 transactivation promotes colorectal cancer aggressiveness through epithelial-mesenchymal transition
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IL-6/STAT3 反式激活异常表达的 Fra-1 通过上皮间质转化促进结直肠癌侵袭性
DOI：
10.1093/carcin/bgv017
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发表时间：
2015-04-01
期刊：
影响因子：
4.7
通讯作者：
Shao, Jimin
中科院分区：
文献类型：
--
作者：
Liu, Hong;Ren, Guoping;Shao, Jimin
肿瘤微环境中的促炎细胞因子白细胞介素-6（IL-6）被认为促进结直肠癌（CRC）的发生和发展。然而，潜在的分子机制仍然难以捉摸。在这项研究中，我们证明了Fos相关抗原-1（Fra-1）在IL-6诱导的CRC侵袭性和上皮-间质转化（EMT）中起着关键作用。在大肠癌细胞系中，发现Fra-1基因的表达在IL-6驱动的EMT过程中显著上调。Fra-1的诱导发生在转录水平上的方式依赖于信号转导和转录激活因子3（STAT 3），在此期间磷酸化和乙酰化的翻译后修饰STAT 3激活直接结合到Fra-1启动子。重要的是，基于RNA干扰的STAT 3或Fra-1的衰减阻止了IL-6诱导的EMT、细胞迁移和侵袭，而Fra-1的异位表达通过调节EMT促进因子（ZEB 1、Snail、Slug、MMP-2和MMP-9）的表达显著逆转了STAT 3敲低效应并增强了CRC细胞的侵袭性。此外，Fra-1水平与229例结直肠癌患者的局部浸润深度以及淋巴结和肝转移呈正相关。在邻近炎性细胞的肿瘤边缘区域观察到Fra-1的强烈免疫组织化学染色，并且与CRC组织中的IL-6分泌和STAT 3活化平行。总之，这项研究提出了异常IL-6/STAT 3/Fra-1信号传导轴的存在，通过EMT诱导导致CRC侵袭性，这表明了恶性疾病的新治疗机会。
The pro-inflammatory cytokine interleukin-6 (IL-6) in tumor microenvironment has been suggested to promote development and progression of colorectal cancer (CRC). However, the underlying molecular mechanisms remain elusive. In this study, we demonstrate that fos-related antigen-1 (Fra-1) plays a critical role in IL-6 induced CRC aggressiveness and epithelial-mesenchymal transition (EMT). In CRC cell lines, the expression of Fra-1 gene was found significantly upregulated during IL-6-driven EMT process. The Fra-1 induction occurred at transcriptional level in a manner dependent on signal transducer and activator of transcription 3 (STAT3), during which both phosphorylated and acetylated post-translational modifications were required for STAT3 activation to directly bind to the Fra-1 promoter. Importantly, RNA interference-based attenuation of either STAT3 or Fra-1 prevented IL-6-induced EMT, cell migration and invasion, whereas ectopic expression of Fra-1 markedly reversed the STAT3-knockdown effect and enhanced CRC cell aggressiveness by regulating the expression of EMT-promoting factors (ZEB1, Snail, Slug, MMP-2 and MMP-9). Furthermore, Fra-1 levels were positively correlated with the local invasion depth as well as lymph node and liver metastasis in a total of 229 CRC patients. Intense immunohistochemical staining of Fra-1 was observed at the tumor marginal area adjacent to inflammatory cells and in parallel with IL-6 secretion and STAT3 activation in CRC tissues. Together, this study proposes the existence of an aberrant IL-6/STAT3/Fra-1 signaling axis leading to CRC aggressiveness through EMT induction, which suggests novel therapeutic opportunities for the malignant disease.