Karyopherin α2 (KPNA2) was reported to be overexpressed and have unfavorable prognostic effects in many malignancies including hepatocellular carcinoma (HCC). Although its contributions to inflammatory response were reported in many studies, its specific associations with immune infiltrations and immune pathways during cancer progression were unclear. Here, we aimed to identify new markers for HCC diagnosis and prognosis through KPNA2-associated immune analyses. RNA-seq expression data of HCC datasets were downloaded from The Cancer Genome Atlas and International Cancer Genome Consortium. The gene expressions were counts per million normalized. The infiltrations of 24 kinds of immune cells in the samples were evaluated with ImmuCellAI (Immune Cell Abundance Identifier). The Spearman correlations of the immune infiltrations with KPNA2 expression were investigated, and the specific positive correlation of B-cell infiltration with KPNA2 expression in HCC tumors was identified. Fifteen genes in KEGG (Kyoto Encyclopedia of Genes and Genomes) B-cell receptor signaling pathway presented significant correlations with KPNA2 expression in HCC. Among them, GRB2 and NRAS were indicated to be independent unfavorable prognostic factors for HCC overall survival. Clinical Proteomic Tumor Analysis Consortium HCC dataset was investigated to validate the results at protein level. The upregulation and unfavorable prognostic effects of KPNA2 and GRB2 were confirmed, whereas, unlike its mRNA form, NRAS protein was presented to be downregulated and have favorable prognostic effects. Through receiver operating characteristic curve analysis, the diagnostic potential of the three proteins was shown. The RNA-binding proteins (RBPs) of KPNA2, NRAS, and GRB2, downloaded via The Encyclopedia of RNA Interactomes, were investigated for their clinical significance in HCC at protein level. An eight-RBP signature with independent prognostic value and dysregulations in HCC was identified. All the RBPs were significantly correlated with MKI67 expression and at least one of KPNA2, GRB2, and NRAS at protein level in HCC, indicating their roles in HCC progression and the regulation of the three proteins. We concluded that KPNA2, GRB2, NRAS, and their RBPs might have coordinating roles in HCC immunoregulation and progression. They might be new markers for HCC diagnosis and prognosis predication and new targets for HCC immunotherapy.

据报道，在许多恶性肿瘤包括肝细胞癌（HCC）中，核转运蛋白α2（KPNA2）过表达并且对患者的预后不良。尽管在许多研究中均报告了其对炎症反应的贡献，但尚不清楚其与癌症进展过程中的免疫浸润和免疫途径的具体联系。在这里，我们旨在通过KPNA2相关的免疫分析为HCC诊断和预后确定新的标志物。HCC数据集的RNA-seq表达数据是从The Cancer Genome Atlas和International Cancer Genome Consortium下载的。基因表达是归一化的每百万计数。用ImmuCellAI（免疫细胞丰度标识符）评估样品中24种免疫细胞的浸润率。研究了免疫浸润与KPNA2表达的Spearman相关性，并鉴定了HCC肿瘤中B细胞浸润​​与KPNA2表达的特异性正相关。KEGG（基因与基因组京都百科全书）B细胞受体信号传导途径中的15个基因与HCC中KPNA2表达密切相关。其中，GRB2和NRAS被认为是肝癌总体生存的独立不利预后因素。研究了临床蛋白质组肿瘤分析协会HCC数据集，以验证蛋白质水平的结果。证实了KPNA2和GRB2的上调和不利的预后作用，然而，不同于其mRNA形式，NRAS蛋白被认为下调并具有良好的预后作用。通过接收器工作特征曲线分析，显示了这三种蛋白的诊断潜力。已下载KPNA2，NRAS和GRB2的RNA结合蛋白（RBP）通过研究了RNA Interactomes百科全书在HCC中蛋白质水平的临床意义。鉴定出具有独立预后价值和肝癌功能异常的八个RBP信号。在肝癌中，所有RBP与MKI67表达以及KPNA2，GRB2和NRAS中的至少一种在蛋白水平上均显着相关，表明它们在肝癌进展和这三种蛋白的调节中的作用。我们得出的结论是，KPNA2，GRB2，NRAS及其RBP可能在HCC免疫调节和进展中具有协调作用。它们可能是HCC诊断和预后预测的新标志物，也是HCC免疫治疗的新目标。