IL6/STAT3/FRA1信号轴驱动的EMT和CSC转录调控网络在结直肠癌侵袭转移中的作用和机制

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.

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。

慢性炎症与结直肠癌（CRC）发生发展密切相关。肿瘤干细胞（CSC）是肿瘤种子细胞。然而，炎性微环境调控肿瘤干细胞可塑性在结直肠癌中的作用和机制仍不清楚。研究阐明炎症微环境对结直肠癌的作用和机制，对于结直肠癌干预和治疗具有重要临床意义。本研究发现和证明：1）肿瘤微环境炎性因子IL6/STAT3信号轴促进结直肠癌细胞FRA1转录及去乙酰化、进而通过调控NANOG促进结直肠癌细胞干性和恶性进展；联合干预肿瘤炎症信号轴和肿瘤干细胞信号通路可以显著抑制结直肠癌恶性进展。2）结直肠癌细胞来源的外泌体具有肝组织趋向性，促进肝组织肿瘤相关巨噬细胞分泌炎性因子IL6、构建肝转移炎性微环境，促进结直肠癌细胞肝转移，为发现干预结直肠癌肝转移的精确药物靶点提供了新的实验和理论依据。3）核糖核酸还原酶在常见类型恶性肿瘤中的表达谱，RR大、小亚基在结直肠癌和肝癌等肿瘤中的作用、表达和活性调控机制，研发了以RR为靶点具有自主知识产权的小分子靶向候选新药。研究成果作为通讯作者和共同通讯作者，在肿瘤领域较高影响因子SCI期刊Oncogene、Carcinogenesis、J Biol Chem、Biochemical Pharmacology、BBA等发表论文5篇；获发明专利授权2项；组织和参加相关国际和国内学术会议交流多次。获后续2020年相关国家自然科学基金面上项目资助（IL6/STAT3炎症信号负调控结直肠癌干细胞新抗原表达促进T细胞免疫逃逸的作用和机制及其干预，主持）。