Table4_Comprehensive analysis on clinical significance and therapeutic targets of LDL receptor related protein 11 (LRP11) in liver hepatocellular carcinoma.DOCX

LDL lipoprotein receptor-related protein 11 (LRP11) plays a role in several tumors. However, their roles in hepatocellular carcinoma remain unclear. The present study aimed to explore the expression profile and prognostic value of LRP11 in liver hepatocellular carcinoma (LIHC) patients using various cancer databases and bioinformatic tools. In bioinformatics analysis, The Cancer Genome Atlas datasets showed increased LRP11 expression in tumor tissues compared to that in non-tumor tissues in various cancers. Moreover, patients with high expression LRP11 correlated with poor prognosis and clinical features. The LRP11 expression positively correlated with the infiltration of immune cells such as macrophages, neutrophils, and myeloid-derived suppressor cells and a combination of high LRP11 expression and high immune infiltrates was associated with the worst survival in LIHC tumors. Our results also indicated that LRP11 expression was closely associated with immune-modulate function, such as antigen presentation. In DNA methylation profiling, hypomethylation of LRP11 is widely observed in tumors and has prognostic value in LIHC patients. Functional enrichment analysis revealed that LIHC-specific LRP11 interacting genes are involved in protein binding, intracellular processing, and G-protein-related signaling pathways. Analyses of drug sensitivity and immune checkpoint inhibitor predict a number of drugs that could potentially be used to target LRP11. In addition, in vitro experiments verified the promoting effect of LRP11 on the migration, invasion, and colony formation capacity of hepatocellular carcinoma cells. Collectively, our results aided a better understanding of the clinical significance of LRP11 in gene expression, functional interactions, and epigenetic regulation in LIHC and suggested that it may be a useful prognostic biomarker for LIHC patients.

低密度脂蛋白受体相关蛋白11（low-density lipoprotein receptor-related protein 11，LRP11）在多种肿瘤中发挥生物学作用，但其在肝细胞癌中的具体功能仍未明确。本研究旨在利用多种癌症数据库及生物信息学工具，探讨肝脏肝细胞癌（liver hepatocellular carcinoma，LIHC）患者体内LRP11的表达谱及其预后价值。生物信息学分析显示，癌症基因组图谱（The Cancer Genome Atlas，TCGA）数据集表明，相较于正常组织，多种癌症的肿瘤组织中LRP11的表达水平显著升高。此外，LRP11高表达的患者与不良预后及临床特征密切相关。LRP11的表达水平与巨噬细胞、中性粒细胞及髓系来源抑制细胞等免疫细胞的浸润程度呈正相关；且在LIHC肿瘤中，LRP11高表达联合高免疫浸润与最差的生存结局显著相关。本研究结果同时显示，LRP11的表达与免疫调节功能（如抗原呈递）密切相关。在DNA甲基化谱分析中，肿瘤组织中广泛存在LRP11的低甲基化现象，且该现象在LIHC患者中具有预后价值。功能富集分析显示，LIHC特异性的LRP11相互作用基因参与了蛋白质结合、细胞内加工及G蛋白相关信号通路的调控。药物敏感性与免疫检查点抑制剂（immune checkpoint inhibitor）分析结果提示，存在多种可靶向LRP11的潜在治疗药物。此外，体外实验验证了LRP11可促进肝细胞癌细胞的迁移、侵袭及集落形成能力。综上，本研究结果有助于进一步阐明LRP11在LIHC中基因表达、功能互作及表观遗传调控方面的临床意义，并提示LRP11或可作为LIHC患者的有效预后生物标志物。