TGF-β1/LINC02036/HES1信号轴促进肝细胞癌侵袭转移的作用及机制研究

Invasion and metastasis are the leading causes of death in hepatocellular carcinoma (HCC) and the main points of scientific research on HCC. Many signaling pathways including TGF-β and Notch pathways involve in HCC progression. The cross-talk between the two pathways promotes HCC invasion and metastasis, but the specific mechanism remains ambiguous. A possible signaling axis ‘TGF-β1/LINC02036/HES1’ was found via bioinformatic analysis. Pre-experiments revealed that TGF-β1 upregulated LINC02036 and LINC02036 upregulated HES1. Our aim is to testify the influence of LINC02036 on HCC by cell research, animal model and clinical analysis. The molecular mechanisms containing the role of TGF-β1 in LINC02036 transcription via Smad and that of LINC02036 in HES1 transcription via histone acetylation modification will be thoroughly investigated. We will validate the effect of the TGF-β1/LINC02036/HES1 axis on EMT, invasion and metastasis in HCC. The study targets finding a new mechanism underlying the link between TGF-β1 pathway and Notch pathway, better understanding the pathogenic mechanism related to HCC and ultimately supplementing new scientific evidence for HCC treatment.

肝癌侵袭转移是其高致死率的关键因素，一直是临床基础研究的重点和难点，众多信号通路参与其中。TGF-β通路和Notch通路可形成串话促进肝癌发展，但其具体机制目前尚不确切。生物信息学分析发现潜在的TGF-β1/LINC02036/HES1信号轴，预实验初步证实TGF-β1可上调LINC02036及LINC02036可上调HES1。本课题将通过细胞实验、动物实验及临床样本数据分析探讨LINC02036在肝癌中的具体效应，着重解析TGF-β1通路经由Smad蛋白调控LINC02036转录表达及LINC02036经由组蛋白乙酰化修饰途径调控HES1转录表达的分子机制，验证TGF-β1/LINC02036/HES1轴在TGF-β1所致肝癌EMT及侵袭转移过程中的作用。本项目旨在通过探寻TGF-β1通路与Notch通路之间关联的新机制，有助于更好地理解肝癌致病机制，为临床治疗肝癌补充新的科学根据。

肝癌侵袭转移是其高致死率的关键因素，一直是临床基础研究的重点和难点，众多信号通路参与其中，TGF-β通路已证实促进肝癌发展。生物信息学分析发现潜在的TGF-β1/Smad3/LINC02036信号轴，实验证实TGF-β1/ Smad3可上调LINC02036表达。本课题通过细胞实验、动物实验及临床样本数据分析探讨LINC02036在肝癌中的具体效应，着重解析TGF-β1通路经由Smad3蛋白调控LINC02036转录表达，LINC02036通过与miR-665竞争性结合，又可上调Smad3表达。LINC02036通过激活Smad3发挥其效应。最后形成一条TGF-β1/Smad3/LINC02036/ Smad3正反馈环路。这一闭环不断得到激活，在TGF-β1所致肝癌EMT及侵袭转移过程中发挥正向作用。本项目通过探寻TGF-β1通路下游新机制，有助于更好地理解肝癌致病机制，为临床治疗肝癌补充新的科学根据。