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Abstract：
Hepatocellular carcinoma (HCC) is among the most common deadly tumors but still lacks specific biomarkers for diagnosis, prognosis, and treatment guidance. The COP9 signalosome (COPS) is an essential regulator of the ubiquitin conjugation pathway upregulated in various cancers. We evaluated the contributions of COPS subunits to HCC tumorigenesis and their utility for prognosis. We comprehensively evaluated the tumor expression pattern and tumorigenic functions of COPS subunits using The Cancer Genome Atlas (TCGA), The Human Protein Atlas and immunohistochemistry. Kaplan-Meier, Cox regression, ROC curve, and nomogram analyses were used to assess the predictive values of COPS subunits for clinical outcome. Expression levels of COPS subunits were significantly upregulated in HCC tissues, which predicted shorter overall survival (OS). Further, Cox regression analysis identified COPS5, COPS7B, and COPS9 as independent prognostic biomarkers for OS. High mutation rates were also found in COPS subunits. Functional network analysis indicated that COPS and neighboring genes regulate \'protein neddylation\', \'protein deneddylation\', and \'protein ubiquitination\'. The COPS PPI included strong interactions with p53, CUL1/2/3/4, and JUN. Moreover, the correlations between COPS subunit expression levels and tumor immune cell infiltration rates were examined using TIMER, TISIDB, ssGSEA, and ESTIMATE packages. COPS subunits expression levels were positively correlated with specific tumor immune cell infiltration rates, immunoregulator expression levels, and microsatellite instability in HCC. Finally, knockout of COPS6 and COPS9 in HCC cells reduced while overexpression enhanced proliferation rate and metastasis capacity. Our study revealed that COPS potential biomarker for unfavorable HCC prognosis and indicators of immune infiltration, tumorigenicity, and metastasis.
摘要：
肝细胞癌（HCC）是最常见的致命性肿瘤之一，但仍然缺乏用于诊断的特异性生物标志物。预后,和治疗指导。COP9信号体(COPS)是多种癌症中上调的泛素结合途径的重要调节因子。我们评估了COPS亚基对HCC肿瘤发生的贡献及其对预后的效用。我们使用癌症基因组图谱（TCGA）全面评估了COPS亚基的肿瘤表达模式和致瘤功能，人类蛋白质图谱和免疫组织化学。Kaplan-Meier,Cox回归,ROC曲线,和列线图分析用于评估COPS亚基对临床结局的预测值.COPS亚基的表达水平在HCC组织中显著上调，预测总生存期(OS)较短。Further,Cox回归分析确定了COPS5、COPS7B、和COPS9作为OS的独立预后生物标志物。在COPS亚基中也发现了高突变率。功能网络分析表明，COPS和邻近基因调节“蛋白质neddylation”，“蛋白质去乙酰化”，和“蛋白质泛素化”。COPSPPI包括与p53、CUL1/2/3/4和JUN的强相互作用。此外，使用TIMER检查COPS亚基表达水平与肿瘤免疫细胞浸润率之间的相关性，TISIB,ssGSEA,和估计包。COPS亚基表达水平与肿瘤特异性免疫细胞浸润率呈正相关,免疫调节剂表达水平，和肝癌的微卫星不稳定性。最后,HCC细胞中COPS6和COPS9的敲除减少，而过表达增强了增殖率和转移能力。我们的研究表明，COPS潜在的生物标志物为不利的HCC预后和免疫浸润的指标，致瘤性，和转移。
