重组tRNA/mir-125b靶向Wnt信号通路逆转肝细胞癌干细胞特性的机制研究

分化水平较差的肝细胞癌（HCC）往往具有早期胚胎干细胞及肝祖细胞的特性，导致耐药、转移和复发，急需探索新的治疗方法。我们的前期研究证明重组pre-microRNAs（tRNA/mirs）代表了可用于癌症治疗研究的新型RNA前药。预实验结果初步表明tRNA/mir-125b可抑制HCC的生长，通过降低HCC干/祖细胞标志物的表达及增强肝成熟标志物的表达调节HCC可塑性，增强HCC标靶药物Sorafenib的敏感性。进一步分析预测Wnt10b为潜在靶基因，据此我们提出假设：tRNA/mir-125b可通过靶向Wnt10b介导的Wnt信号通路抑制肝癌细胞的干细胞特性，进而抑制HCC的生长、转移和耐药。本项目拟利用类器官培养和肝癌PDX小鼠模型和脾脏注射肝转移模型研究tRNA/mir-125b对HCC干细胞特性动态转化过程的调控及机制，并探讨tRNA/mirs作为HCC治疗新策略的潜在应用价值。

Hepatocellular carcinoma(HCC) with poor differentiation is usually characterized with embryonic stem cells or liver progenitor cells properties, which lead to chemoresistance, metastasis and relapse. There is an urgent need to investigate new therapeutic strategies for HCC. Our previous studies have highlighted the recombinant pre-microRNAs(tRNA/mirs) represent a novel RNA prodrug for cancer therapies. Our preliminary data found that tRNA/mir-125b could inhibit HCC growth, regulate HCC plasticity by reducing the expression of HCC stem/progenitor cell markers while increasing the expression of mature hepatocyte markers, and enhance the sorafenib sensitivity. Further investigation found that Wnt10b was the potential target of tRNA/mir-125b. Thus, we suppose that tRNA/mir-125b may inhibit HCC stem cell properties via suppressing Wnt10b mediated Wnt signaling pathway, further downgrade HCC tumor growth, metastasis and chemoresistance. We’re going to employ organoid, PDX and intrasplenic injection models to uncover tRNA/mir-125b in regulating the dynamic transformation process of HCC stem cell properties and the underlying mechanism, further explore the application of tRNA/mirs as novel therapeutic strategies for HCC treatment.