METTL3通过m6A修饰介导lnc-TSPAN12结合PSPC1蛋白促进肝细胞癌EMT和侵袭转移的机制研究

lncRNA在肿瘤侵袭转移过程中发挥着关键作用，但其在肝细胞癌（HCC）中的生物学功能和分子机制仍有待阐明。我们前期发现lnc-TSPAN12在HCC中高表达，原因可能与METTL3介导的m6A修饰提高其稳定性有关。敲低lnc-TSPAN12可显著抑制HCC细胞的迁移、侵袭及上皮间质转化（EMT）过程。进一步研究发现lnc-TSPAN12可与TGF-β1通路的关键调控因子PSPC1结合并上调其蛋白表达水平，提示lnc-TSPAN12可能通过调控PSPC1蛋白激活TGF-β1通路，进而促进HCC发生EMT及侵袭转移。在此基础上，本课题拟进一步明确lnc-TSPAN12/PSPC1在HCC侵袭转移过程中的生物学功能；阐明METTL3通过m6A修饰介导lnc-TSPAN12结合PSPC1促进HCC发生EMT及侵袭转移的分子机制。本项目的实施有望为临床HCC转移的预警和治疗提供新的思路和潜在靶点。

Long non-coding RNAs have been demonstrated to play vital roles in the tumor metastasis, but their biological functions and molecular mechanisms have not been clarified. Our preliminary results showed that lnc-TSPAN12 was highly expressed in hepatocellular carcinoma (HCC), which was possibly due to its stability improvement through METTL3-mediated m6A modification. Knockdown of lnc-TSPAN12 significantly inhibited HCC cell migration, invasion and epithelial-mesenchymal transition (EMT) process. Further studies indicated that lnc-TSPAN12 can directly bind to PSPC1 protein, a key switch that activates TGFβ1 pathway, and up-regulate its protein expression level. The above results suggested that lnc-TSPAN12 may activate TGFβ1 pathway by regulating PSPC1 protein, thus promoting EMT, invasion and metastasis of HCC. In this project, we will further clarify the biological function of lnc-TSPAN12/PSPC1 in the process of HCC invasion and metastasis. Additionally, we will elucidate the molecular mechanism by which METTL3 mediated lnc-TSPAN12 binding to PSPC1 through m6A modification to promote EMT, invasion and metastasis of HCC. The implementation of this project is expected to provide new ideas and potential targets for the early warning and treatment of clinical HCC metastasis.