RhoB/Arl14小G蛋白中心功能聚合体通过Slit2/Robo1-Wnt/β-catenin通路轴调节大肠癌EMT

Treatment resistance and metastasis are the major causes of death in patients with colorectal cancer, and epithelial-mesenchymal transition (EMT) is an important part of the regulation of tumor therapy resistance and metastasis. We found that RhoB may be involved in colorectal cancer radiotherapy resistance and metastasis as a "hub" molecule through regulating EMT. However, the mechanism by which RhoB regulates EMT through upstream and downstream pathways is unknown. Based on bioinformatics analysis and preliminary experimental results, we propose the theoretical hypothesis that RhoB / Arl14 small G protein central regulatory hub can regulate EMT in colorectal cancer via Slit2 / Robo1-Wnt / β-catenin pathway axis. This project will further study the synergistic effect of RhoB and Arl14, two small G proteins, on the basis of the previous work, from three aspects of expression-related, activity-related, and function-related; elucidate the specific regulation mechanism of RhoB / Arl14 on Wnt / β-catenin pathway from the identification of intermediate molecules, nuclear translocation of β-catenin and activation of transcription factors by using RNA-seq high throughput sequencing and other techniques; identify the specific GAP molecules directly binding Slit2 / Robo1 and RhoB / Arl14 and investigate their functional relevance. This study will help to enrich the mechanism of EMT in colorectal cancer and provide a theoretical basis for the development of new molecular drugs for colorectal cancer targeting RhoB / Arl14 small G protein central regulatory hub.

治疗抵抗和转移是大肠癌病人致死的主要原因，而上皮间质转化(EMT)是调控肿瘤治疗抵抗及转移的重要环节。我们发现RhoB可能作为调控大肠癌EMT的枢纽分子，参与了大肠癌放疗抵抗及转移。然而，RhoB调控肿瘤EMT的机制不明。根据生信分析及预实验结果，我们提出了RhoB/Arl14小G蛋白中心功能聚合体通过Slit2/Robo1-Wnt/β-catenin通路轴调节大肠癌EMT的理论假设。本项目拟进一步研究RhoB与Arl14这两种小G蛋白的协同作用；利用高通量测序等技术，从中间分子鉴定等方面阐明RhoB/Arl14对Wnt/β-catenin通路的具体调控机制；利用免疫共沉淀技术明确直接连接Slit2/Robo1和RhoB/Arl14的GAP分子，并研究它们直接功能相关性。本研究将有助于丰富大肠癌EMT的机制，为针对RhoB/Arl14 小G蛋白功能聚合体开发大肠癌分子靶向药物提供依据。

治疗抵抗和转移是大肠癌病人致死的主要原因，而上皮间质转化(EMT)是调控肿瘤治疗抵抗及转移的重要环节。项目组通过探索RhoB参与大肠癌放疗耐药的具体机制，证实了RhoB通过Akt和FOXM1通路在大肠癌放疗耐药中发挥关键作用。项目组通过探索RhoB与Rab1A的相互作用及其形成小G蛋白中心功能聚合体后对于结肠癌细胞EMT的调控作用，证实了RhoB/Rab1A小G蛋白中心功能聚合体促进结肠癌细胞的EMT，进一步扩充了RhoB的作用网络，丰富了结肠癌EMT的机制，为针对RhoB/Rab1A小G蛋白功能聚合体开发大肠癌分子靶向药物提供依据。项目组还通过探索Arl和SRGAP家族成员在消化道肿瘤中的表达及预后情况，证实了SRGAP2高表达与肝癌预后负相关，其可能通过肿瘤代谢通路参与调控肝癌生物学行为；证实了Arl4C在胃癌中的高表达及其对于胃癌恶性表型的促进作用，发现Arl4C可能是胃癌患者TGF-β1靶向治疗的辅助靶点，为Arl4C作为胃癌生物标志物及治疗靶点提供理论依据。