LncRNA uc.306调控Wnt/β-catenin通路抑制肝癌侵袭转移的机制研究

转移是肝癌高致死率的主要原因之一。目前已知上皮-间质转化（EMT）过程在肿瘤转移过程中发挥重要作用，但关于其在肝癌中的具体调控机制仍然有许多问题尚未阐明。近年来越来越多研究发现长链非编码RNA（lncRNA）在肿瘤发生发展的各个阶段发挥重要作用，也包括对EMT过程的调控。本课题前期通过芯片分析比较了肝癌转移样本和原位肝癌样本中差异表达的lncRNA，发现超级保守lncRNA uc.306在转移样本中有明显的低表达，uc.306可与β-TRCP相互作用且它们之间的表达呈负相关，而β-TRCP底物之一就是EMT过程的关键调控蛋白β-catenin。因此我们提出科学假设：lncRNA uc.306通过与β-TRCP相互作用并抑制其表达从而下调Wnt/β-catenin通路活性抑制肝癌细胞EMT进程最终抑制肝癌细胞侵袭转移。本项目将为肝癌的临床诊断、筛查及治疗提供新的可能标志物或靶点。

Metastasis has been the major reason for the malignant progression of hepatocellular carcinoma (HCC). It is well-known that Epithelial-mesenchymal transition (EMT) is the key process in cancer metastasis progression. Although the importance of EMT in HCC is already well-studied, the underlying mechanism which drives EMT process in HCC still elusive. Our preliminary data show that the ultraconserved lncRNA uc.306 is obviously downregulated in metastasis HCC tumor samples. Moreover, the bioinformatics analysis indicates that lncRNA uc.306 may interact with E3 ubiquitin ligase β-TRCP. Interestingly, one of β-TRCP’s target protein is β-catenin, which is the key player in EMT procession. These results suggesting that lncRNA uc.306 may regulate Wnt/ β-catenin pathway by downregulating β-TRCP expression that in turn repress HCC metastasis. If successful, lncRNA uc.306 may serve as a novel biomarker or therapeutic target for HCC.