Abstract
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.
Highlights
Liver cancer is the seventh most common cancer and the third leading cause of cancer death worldwide (Bray et al, 2018)
KPNA2 was shown to be a trigger of interleukin 6 (IL-6) secretion, colocalized with T cells and neutrophils, and could be upregulated via tumor necrosis factor α stimulation (Liu et al, 2015)
We evaluated the correlations between KPNA2 expression and infiltrations of 24 kinds of immune cells in Hepatocellular carcinoma (HCC) tumors and normal liver tissues from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) HCC datasets to identify the specific correlations between KPNA2 expression and immune infiltration in HCC tumors in contrast to those in normal liver tissues
Summary
Liver cancer is the seventh most common cancer and the third leading cause of cancer death worldwide (Bray et al, 2018). Hepatocellular carcinoma (HCC) is the predominant type of primary liver malignancies, with a 5-year overall survival (OS) rate of less than 20%, mainly due to its late diagnosis. It was reported that for patients with early-stage HCC, the 5-year survival rate was greater than 70% (Siegel et al, 2018), much better than that of latestage patients, calling for effective markers of its early diagnosis and prognostic predication. It was demonstrated to play crucial roles in the negative regulation of regulatory T cells (Tregs) differentiation through its interaction and translocation of proinflammatory molecule NLRP3 (Park et al, 2019). In a study of vaccinia virus (VACV), the positive effects of KPNA2 on immunoregulation was shown in the induction of VACV specific CD8+ T-cell memory via its interaction with p65 (Pallett et al, 2019). KPNA2 downregulation was reported to be associated with enterovirus 71-induced innate immune response (Peng et al, 2018), indicating its negative immunoregulatory roles
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