Pan Shen, Zhan Yunhong, Chen Xiaonan, Wu Bin, Liu Bitian
Department of Radiology, Shengjing Hospital of China Medical University, Shenyang, China.
Department of Urology, Shengjing Hospital of China Medical University, Shenyang, China.
Front Oncol. 2019 Jul 4;9:613. doi: 10.3389/fonc.2019.00613. eCollection 2019.
Stem cells characterized by self-renewal and therapeutic resistance play crucial roles in bladder cancer (BLCA). However, the genes modulating the maintenance and proliferation of BLCA stem cells are still unclear. In this study, we aimed to characterize the expression of stem cell-related genes in BLCA. The mRNA expression-based stemness index (mRNAsi) of The Cancer Genome Atlas (TCGA) was evaluated and corrected by tumor purity. Corrected mRNAsi were further analyzed with regard to muscle-invasive bladder cancer molecular subtypes, survival analysis, pathological staging characteristics, and outcomes after primary treatment. Next, weighted gene co-expression network analysis was used to find modules of interest and key genes. Functional enrichment analysis was performed to functionally annotate the modules and key genes. The expression levels of key genes in all cancers were validated using Oncomine and Gene Expression Omnibus (GEO) database containing molecular subtypes in BLCA. Protein interaction networks were used to identify upstream genes, and the relationships between genes were analyzed at the protein and transcription levels. mRNAsi was significantly upregulated in cancer tissues. Corrected mRNAsi in BLCA increased as tumor stage increased, with T3 having the highest stem cell characteristics. Lower corrected mRNAsi scores had better overall survival and treatment outcome. The modules of interest and key genes were determined based on topological overlap measurement clustering results and the inclusion criteria. For 13 key genes (, and ), enriched gene ontology terms related to cell proliferation (e.g., mitotic nuclear division, spindle, and microtubule binding) were determined. Their expression did not differ according to the pathological stages of BLCA, and these genes were clearly overexpressed in many types of cancers. In GEO database, the expression levels of 13 key genes were higher in basal subtype with the highest stem cell characteristics than in luminal and its subtypes. and may be regulated upstream of other key genes, and the key genes were found to be strongly correlated with each other and with upstream genes. The 13 key genes identified in this study were found to play important roles in the maintenance of BLCA stem cells. Controlling the upstream genes and may have applications in the treatment of BLCA. These genes may act as therapeutic targets for inhibiting the stemness characteristics of BLCA.
以自我更新和治疗抗性为特征的干细胞在膀胱癌（BLCA）中起着至关重要的作用。然而，调节BLCA干细胞维持和增殖的基因仍不清楚。在本研究中，我们旨在表征BLCA中干细胞相关基因的表达。通过肿瘤纯度评估并校正了癌症基因组图谱（TCGA）基于mRNA表达的干性指数（mRNAsi）。对校正后的mRNAsi进一步进行肌肉浸润性膀胱癌分子亚型、生存分析、病理分期特征及初始治疗后结果的分析。接下来，使用加权基因共表达网络分析来寻找感兴趣的模块和关键基因。进行功能富集分析以对模块和关键基因进行功能注释。使用包含BLCA分子亚型的Oncomine和基因表达综合数据库（GEO）验证所有癌症中关键基因的表达水平。利用蛋白质相互作用网络鉴定上游基因，并在蛋白质和转录水平分析基因之间的关系。mRNAsi在癌组织中显著上调。BLCA中校正后的mRNAsi随着肿瘤分期增加而升高，T3期具有最高的干细胞特征。校正后的mRNAsi得分较低者总体生存率和治疗效果更好。基于拓扑重叠测量聚类结果和纳入标准确定了感兴趣的模块和关键基因。对于13个关键基因（……），确定了与细胞增殖相关的富集基因本体术语（如，有丝分裂核分裂、纺锤体和微管结合）。它们的表达根据BLCA的病理分期没有差异，并且这些基因在多种癌症中明显过表达。在GEO数据库中，13个关键基因在具有最高干细胞特征的基底亚型中的表达水平高于管腔亚型及其各亚型。……可能在其他关键基因的上游受到调控，并且发现关键基因彼此之间以及与上游基因强烈相关。本研究中鉴定出的13个关键基因在维持BLCA干细胞方面发挥重要作用。控制上游基因……可能在BLCA治疗中具有应用价值。这些基因可能作为抑制BLCA干性特征的治疗靶点。
