癌基因PTOV1增强肝癌干细胞样表型的分子机制

A large number of studies have shown that tumor has cancer stem cells (CSCs), which are thought to be the basis of tumor occurrence, development and maintenance. Recent evidence demonstrated that tumor stem cells also play important roles in tumor survival, metastasis, drug resistance and relapse. However, the regulation mechanisms underlying self-renewal of CSCs are still not clear. Our previously published data demonstrated that PTOV1 is upregulated in hepatocellular carcinoma (HCC) cells, and high expression of PTOV1 is closely correlated with poor prognosis of patients. In our recent study, we found that over-expression of PTOV1 could induce EMT and promote the self-renewal of CSCs in HCC. Moreover, we found that PTOV1 could activate Wnt/β-catenin signaling pathway via interaction with β-catenin, thus leading to upregulation of the expression of target genes c-myc, Snail and stem cell markers CD133, CD90 as well as EpCAM. In our current study, we will further delineate the molecular mechanism of PTOV1 in regulation of CSCs self-renewal, demonstrate the functional role of PTOV1 in the progresssion of HCC both in vivo and in vitro, and investigate the clinical relevance of PTOV1 in metastasis and recurrence of HCC. Our study may help indentify a novel prognostic factor and therapeutic target for HCC.

近年研究表明肿瘤干细胞是肿瘤发生、发展与维持的基础，在肿瘤的存活、转移、耐药与复发中发挥着重要的作用，然而肿瘤干细胞自我更新的调控机制仍不清楚。前期我们已发表的文章报道癌基因PTOV1在肝癌中表达显著增高，且其高表达与肝癌病人的不良预后密切相关。进一步研究我们发现高表达PTOV1可诱导肝癌细胞发生EMT，并增强肝癌肿瘤干细胞自我更新的能力。同时我们预实验结果显示PTOV1可与β-catenin相互结合而激活Wnt/β-catenin信号通路，从而上调靶基因c-myc，Snail以及干细胞标记物CD133，CD90，EpCAM等的表达。因此，本项目将在前期预实验的基础上，通过体内体外研究系统，深入探讨PTOV1增强肝癌干细胞样表型的分子机制并揭示其在肝癌进展中的生物学功能，并结合临床标本，分析PTOV1的表达与肝癌转移和复发的相关性，有望为肝癌的转移和复发提供新的预后因子及治疗靶标。

肿瘤干细胞( cancer stem cells, CSCs)是肿瘤组织中具有自我更新能力并能不断分化产生异质性肿瘤的一小部分癌细胞亚群。肿瘤干细胞具有极强的成瘤能力，也被称为肿瘤启动细胞（tumor initiating cells, TICs），是肿瘤发生、发展与维持的基础。Wnt/β-catenin信号通路是肝癌干细胞重要通路，研究肝癌Wnt/β-catenin信号通路过度激活的价值至关重要。多核型髓系抑制细胞（PMN-MDSC）在肿瘤侵袭转移中发挥重要作用，其免疫抑制作用众所皆知，但其对肿瘤细胞的直接调控作用尚待阐明。近期我们发现LOX-1是人PMN-MDSC的特异性标记（Nature medicine 2018，Immunology 2017），并证实外周血LOX-1+PMN-MDSC水平与肝癌预后及临床分期高度相关。进而发现LOX-1+PMN-MDSC可上调肝癌PLA2G4B表达、激活Wnt/β-catenin通路诱导EMT，增强肿瘤侵袭和转移可能是其机制。未来我们拟明确LOX-1+PMN-MDSC诱导肝癌侵袭转移的具体调控机理，以PLA2G4B为核心，明确其上下游调控因子，找到其调控β-catenin的分子机制，最终结合临床标本，分析LOX-1+PMN-MDSC及关键蛋白与肝癌转移的相关性，本研究有望为肝癌的侵袭和转移提供新的预后因子及治疗靶标。