KPNA2-Associated Immune Analyses Highlight the Dysregulation and Prognostic Effects of GRB2, NRAS, and Their RNA-Binding Proteins in Hepatocellular Carcinoma

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 Zhang et al. KPNA2-Associated Immune Analyses in HCC Frontiers in Genetics | www.frontiersin.org 2 October 2020 | Volume 11 | Article 593273 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.

Identification of Hypoxia–Immune-Related Gene Signatures and Construction of a Prognostic Model in Kidney Renal Clear Cell Carcinoma

“…As for the immune status, we adopted the ImmuCellAI method to calculate the infiltration of immune cells in KIRC samples. This method supported the ssGSEA enrichment score of expression deviation profile per cell type and has been widely used in cancer research, including pituitary adenomas, hepatocellular carcinoma, sarcoma, and lung adenocarcinoma ( Wang et al, 2020a ; Zhang et al, 2020b ; Hu et al, 2021 ; Zhao et al, 2021 ). We successfully clustered the KIRC patients into different groups by hypoxia and immune status using these combined methods.…”

Identifying a Novel Endoplasmic Reticulum-Related Prognostic Model for Hepatocellular Carcinomas

“…A set of immune cell infiltration-associated genes reportedly showed a prognostic effect for HCC patients [ 33 , 47 ]. KPNA2 expression was also positively correlated with the immune infiltration levels of B cells in HCC tissues [ 48 ]. In the present study, we investigated the microenvironmental infiltration feature for the ER model-based high/low risk groups of HCC cases through two algorithms, namely, “ESTIMATE” and “CIBERSORT.” The immune cells and stroma are the two main kinds of nontumor components within the tumour microenvironment [ 22 ].…”

circRanGAP1/miR-27b-3p/NRAS Axis may promote the progression of hepatocellular Carcinoma

“…KEGG analysis also suggested that the MAPK signaling pathway may be a potential downstream pathway for circRanGAP1. Furthermore, previous studies have identified NRAS as an immune-related gene that induces tumorigenesis by altering the immune microenvironment [20][21][22]. Therefore, we hypothesized that circRANGAP1 accelerated the HCC progression by regulating miR-27b-3p/NRAS axis, activating the downstream MAPK signaling pathway, and affecting the infiltration levels of tumor-associated macrophages.…”