白介素6（IL6）是多种肿瘤中的主要促肿瘤炎症因子，可由炎症细胞和肿瘤细胞等产生。我们前期研究发现，IL6/STAT3/FRA1信号通路调控上皮-间质转化（EMT）促进结直肠癌（CRC）侵袭转移，并与肿瘤干细胞（CSC）可塑性调控相关。我们推测，FRA1可能作为促肿瘤炎症因子信号轴的枢纽转录因子、与EMT诱导转录因子（EMT-TFs）和CSC诱导转录因子（CSC-TFs）组成核心调控程序，驱动CRC侵袭转移。本项目拟在具有EMT表型、同时具有EMT和CSC表型和亲本CRC细胞上，分析IL6/STAT3/FRA1、EMT-TFs和CSC-TFs三者之间的相互转录调控网络结构、关键节点分子和调控机制，与其它EMT和CSC调控通路的交互作用，并应用裸鼠移植瘤和临床样本验证，阐明促肿瘤炎症因子IL6/STAT3/FRA1信号轴通过调控EMT和CSC可塑性促进CRC侵袭转移的作用、机制和临床意义。

Interleukin 6 (IL6) is one of the major tumor-promoting inflammatory cytokines produced by tumor cells, infiltrating leukocytes and other stromal cells in many cancers. Our previous studies demonstrate that the aberrantly expressed FRA1 by IL6/STAT3 transactivation promotes colorectal cancer (CRC) invasion and metastasis through epithelial-mesenchymal transition (EMT), in which cancer stem cell (CSC) plasticity regulation may also be involved. Combined with literature reports and ONCOMINE and TCGA datamining, we hypothesize that during the IL6/STAT3/FRA1 signaling axis – driven CRC development, FRA1 could be the pivot transcription factor (TF) to coordinate with EMT-TFs and CSC-TFs　to facilitate cancer cell dissemination. In the present proposed study, by using CRC cells with EMT phenotypes, CRC cells with both EMT and CSC phenotypes, and the parental CRC cells, we will analyze the IL6/STAT3/FRA1 signaling axis – driven transcriptional regulatory network among FRA1, EMT-TFs and CSC-TFs, the key regulators and interacting mechanisms, and their possible crass-talks with other EMT and CSC signaling pathways. The in vitro data will be validated in NOD/SCID mouse xenografts and clinical CRC specimens. The clarification of the action and mechanisms of the tumor-promoting inflammatory cytokine IL6/STAT3/FRA1 signaling axis - driven transcriptional regulatory network for EMT and CSC plasticity in CRC may lead to the identification of novel precision therapeutic targets for the prevention and treatment of CRC metastasis.