TGF-β/lnc-APUE/ZEB1通路促进肝癌转移的机制及生物学意义

LncRNAs是一类长度大于200 nt且不能编码蛋白的分子，参与调控多种生物学过程。侵袭转移是肿瘤病人死亡的主要原因，TGF-β信号通路和上皮间质转化（EMT）是促进转移的重要环节，但lncRNAs在其中的作用机理尚不清楚。我们的前期研究显示：TGF-β/SMAD信号通路可转录激活lnc-APUE的表达；Lnc-APUE促进肝癌细胞的迁移和侵袭；敲低lnc-APUE可抑制ZEB1的表达并提高E-cadherin的表达水平。基于此，我们提出TGF-β诱导表达的lnc-APUE通过ZEB1促进肝癌转移的假说。本项目拟结合体内外模型，鉴定lnc-APUE对肝癌转移的调控作用；揭示lnc-APUE发挥作用的分子机制；揭示TGF-β/lnc-APUE/ZEB1通路对肝癌转移的调控作用。研究结果将阐明lnc-APUE的生物学功能和调控网络，揭示肝癌转移新机制，为发展新型肿瘤防治策略提供新靶点。

LncRNAs are transcripts longer than 200 nt and lack protein-coding ability. Growing evidence indicates that lncRNAs regulate different physiological and pathological processes. The invasion and metastasis of cancer is the main cause of patient death. TGF-β signaling and epithelial-mesenchymal transition (EMT) play important roles in tumor metastasis, but the implication of lncRNA in this process is unclear. Our preliminary results showed that TGF-β induced lnc-APUE transcription, while lnc-APUE increased tumor cell migration and invasion, and silencing lnc-APUE decreased the protein level of ZEB1 and upregulated the level of E-cadherin. Based on these findings, we proposed that the TGF-β-regulated lnc-APUE may promote tumor metastasis through regulating ZEB1. In this study, we will elucidate this hypothesis using in vivo and in vitro models: 1. Disclose the role of lnc-APUE in tumor metastasis. 2. Clarify its underlying mechanism. 3. Reveal the role of TGF-β/lnc-APUE/ZEB1 axis on tumor metastasis. The results will extend our understanding on the biological function and regulation network of lnc-APUE and on the mechanisms of tumor metastasis, and provide new targets for anticancer therapy.