Sang Xiaopu, Wu Fenfang, Wu Di, Lin Shan, Li Jingyi, Zhao Nan, Chen Xiaoni, Xu Anlong
School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China.
Department of Central Laboratory, Shenzhen Hospital, Beijing University of Chinese Medicine, Shenzhen, China.
Front Genet. 2020 Feb 28;11:112. doi: 10.3389/fgene.2020.00112. eCollection 2020.
Several markers have been reported to be specific for hepatic cancer stem cells (HCSCs), which is usually thought to be highly associated with poor clinical outcomes. Tumor-infiltrating immune cells act as an important factor for oncogenesis. Little is known about the correlation of HCSC markers to prognosis and immune infiltrates.
Expression of HCSC markers was analyzed through Oncomine database, Gene Expression Profiling Interactive Analysis (GEPIA) and Integrative Molecular Database of Hepatocellular Carcinoma (HCCDB), respectively. The prognostic effect of HCSC markers was evaluated using Kaplan-Meier plotter in association with different tumor stages, risk factors, and gender. The correlation of HCSC markers to tumor-infiltrating immune cells was tested by Tumor Immune Estimation Resource (TIMER). HCSC markers related gene sets were investigated by GEPIA, with their biological functions being analyzed by Cytoscape software.
The expression level of 10 HCSC markers in HCC was higher than that in normal tissues in at least one database. Among them, high expression of , and was positively correlated with poor prognosis (: OS = 0.0012, PFS = 7.9E-05. : OS = 0.012. : OS = 0.0004, PFS = 0.0013, respectively). However, the expression of , and was associated with prolonged OS and PFS. was significantly upregulated in poor prognosis of HCC patients with different conditions. Besides, total nine HCSC markers were identified to be positively associated with immune infiltration, including . Furthermore, Toll-like receptor signaling pathway was found to be one major pathway of these HCSC markers related gene networks.
Our results suggest that seven upregulated HCSC markers (, , , , and ) are related with poor prognosis and immune infiltration in HCC. In addition, we find that high expression remarkably affect prognosis in male HCC patients but not in female. HCC patients under viral infection or alcohol intake with increased expression had poorer prognosis. Therefore, HCSCs markers likely play an important role in tumor related immune infiltration and might be a potential therapeutic target in patients with HCC.
已有多种标志物被报道为肝癌干细胞（HCSCs）所特有，通常认为其与不良临床预后高度相关。肿瘤浸润免疫细胞是肿瘤发生的一个重要因素。关于HCSC标志物与预后及免疫浸润之间的相关性，目前所知甚少。
分别通过Oncomine数据库、基因表达谱交互分析（GEPIA）和肝细胞癌综合分子数据库（HCCDB）分析HCSC标志物的表达。使用Kaplan-Meier绘图仪结合不同肿瘤分期、危险因素和性别评估HCSC标志物的预后作用。通过肿瘤免疫估计资源（TIMER）检测HCSC标志物与肿瘤浸润免疫细胞的相关性。通过GEPIA研究与HCSC标志物相关的基因集，并利用Cytoscape软件分析其生物学功能。
在至少一个数据库中，10种HCSC标志物在肝癌中的表达水平高于正常组织。其中， 、 和 的高表达与不良预后呈正相关（：总生存期[OS] = 0.0012，无进展生存期[PFS] = 7.9E - 05。：OS = 0.012。：OS = 0.0004，PFS = 0.0013，分别）。然而， 、 和 的表达与OS和PFS的延长相关。 在不同情况的肝癌患者不良预后中显著上调。此外，共鉴定出9种HCSC标志物与免疫浸润呈正相关，包括 。此外，Toll样受体信号通路被发现是这些与HCSC标志物相关基因网络的主要通路之一。
我们的结果表明，7种上调的HCSC标志物（ 、 、 、 、 和 ）与肝癌的不良预后和免疫浸润相关。此外，我们发现 高表达对男性肝癌患者的预后有显著影响，而对女性则无影响。病毒感染或饮酒且 表达增加的肝癌患者预后较差。因此，HCSCs标志物可能在肿瘤相关免疫浸润中起重要作用，并且 可能是肝癌患者的潜在治疗靶点。
