我们前期研究发现：双表型肝细胞癌(DPHCC)表达胆管CK19分子、具有肝祖细胞特征和高复发风险、肝祖细胞的增殖受Wnt通路调控、从术后复发肝癌筛选出miR-483-5p高表达，预测靶基因CacyBP与Wnt信号通路活性相关，这些结果为探讨miRNA-靶基因-Wnt通路轴调控DPHCC双向分化的分子机制提供了新思路。为此，本课题拟通过调控DPHCC细胞miR-483-5p和CacyBP的表达，明确对Wnt通路关键分子的调控路径及对CK19表型及侵袭能力的影响；检测100例DPHCC中miR-483-5p、CacyBP和Wnt通路关联分子的表达特点，并与预后和生物学特性的相关性进行统计学分析。本研究有望率先提出DPHCC类型相关miRNA-靶基因-Wnt信号通路轴、阐明其调控双表型特性与双重生物学行为的分子机制、提出有潜在诊治价值的分子靶标、明确DPHCC亚型对制订个体化诊疗策略的指导意义。

We previously found that dual-phenotype hepatocellular carcinoma (DPHCC) can express both hepatocellular biomarkers(AFP/Hep Par-1) and biliary biomarkers(CA19-9/CK19), and showed the characteristics of hepatic progenitor cells (HPCs) with highly postoperative recurrent risk; HPCs were activited with highly proliferation activity by the activation of Wnt signaling pathway.By microRNAs screening assay, we firstly found that the expression of miR-483-5p was significantly increased in the postoperative recurrent HCC,ite target gene,CacyBP was also related to the activity of Wnt pathway.The above results reasonably leading to the hypothesis that miR-483-5p, through its target gene of CacyBP, regulates the activity of Wnt/β-catenin pathway, which may present the molecular mechanism underlying the regulation of DPHCC's bidirectional differentiation through miR-483-5p-CacyBP-Wnt/β-catenin signaling pathway axis. Therefore, in the present study, our aims are: (a). to clarify that CacyBP suppression by miR-483-5p accounts for Wnt/ β-catenin hyperactivation,and the miR-483-5p- CacyBP-Wnt/β-catenin-dependent pathway might enhance CK19 expression and the invasive ability of DPHCC cells; (b).to confirm the correlation among the expressions of key moleculars of Wnt/β-catenin pathway, miR-483-5p and its target gene CacyBP in DPHCC cells and DPHCC tissues; (c).and to establish the molecular phenotype by analyzing the association of the above molecular expressions with tumor bioloical behaviours and clinicopathological features, including long-term prognoses in 200 patients with DPHCC. This project holds great promises to firstly discover special miR483-5p-CacyBP-Wnt/β-catenin signaling cascade for regulating the dual genetic phenotypes of DPHCC,clarifies the molecular mechanism in regulating the double- phenotype characteristics and biological behaviours of DPHCC, provides the molecular targets with potential diagnostic and therapeutic values, and explicits the significance of DPHCC submolecular classification in determining the new individualized therapeutic strategy.