Comprehensive analysis of karyopherin alpha family expression in lung adenocarcinoma: Association with prognostic value and immune homeostasis

Abstract

Background: Karyopherin alpha (KPNA), a nuclear transporter, has been implicated in the development as well as the progression of many types of malignancies. Immune homeostasis is a multilevel system which regulated by multiple factors. However, the functional significance of the KPNA family in the pathogenesis of lung adenocarcinoma (LUAD) and the impact of immune homeostasis are not well characterized.Methods: In this study, by integrating the TCGA-LUAD database and Masked Somatic Mutation, we first conducted an investigation on the expression levels and mutation status of the KPNA family in patients with LUAD. Then, we constructed a prognostic model based on clinical features and the expression of the KPNA family. We performed functional enrichment analysis and constructed a regulatory network utilizing the differential genes in high-and low-risk groups. Lastly, we performed immune infiltration analysis using CIBERSORT.Results: Analysis of TCGA datasets revealed differential expression of the KPNA family in LUAD. Kaplan-Meier survival analyses indicated that the high expression of KPNA2 and KPNA4 were predictive of inferior overall survival (OS). In addition, we constructed a prognostic model incorporating clinical factors and the expression level of KPNA4 and KPNA5, which accurately predicted 1-year, 3-years, and 5-years survival outcomes. Patients in the high-risk group showed a poor prognosis. Functional enrichment analysis exhibited remarkable enrichment of transcriptional dysregulation in the high-risk group. On the other hand, gene set enrichment analysis (GSEA) displayed enrichment of cell cycle checkpoints as well as cell cycle mitotic in the high-risk group. Finally, analysis of immune infiltration revealed significant differences between the high-and low-risk groups. Further, the high-risk group was more prone to immune evasion while the inflammatory response was strongly associated with the low-risk group.Conclusions: the KPNA family-based prognostic model reflects many biological aspects of LUAD and provides potential targets for precision therapy in LUAD.

The Pro-Oncogenic Sphingolipid-Metabolizing Enzyme β-Galactosylceramidase Modulates the Proteomic Landscape in BRAF(V600E)-Mutated Human Melanoma Cells

“…Immune system evasion represents a hallmark of melanoma progression [ 47 ]. Our data indicate that, besides CD73, GALC transduction induces an increase in the levels of the importin karyopherin subunit alpha 4, kynureninase, and RNA-binding motif protein 12, all involved in tumor immune escape [ 19 , 20 , 28 ]. In keeping with a possible role for alterations in the sphingolipid metabolism in immune evasion, sphingolipid pathway enzymes have been shown to modulate immune cell function in cancer [ 48 ], sphingomyelin appears to play a key role in tumor progression and immune evasion [ 49 ], and neutral sphingomyelinase 2 expression impairs melanoma growth by enhancing CD8+ T-cell responses [ 50 ].…”

“…Karyopherins, or importins, are cytoplasmic proteins that recognize NLSs and dock NLS-containing proteins to the nuclear pore complex. Oncosuppressor involved in tumor immune escape [19].…”

LncRNA SNHG6 Upregulates KPNA5 to Overcome Gemcitabine Resistance in Pancreatic Cancer via Sponging miR-944

“…Karyopherin alpha (KPNA) 5 is known as a protein cargo to import proteins into the nucleus [ 27 ]. KPNA5 functions as an adaptor molecule that carries protein cargoes carrying the nuclear localization signal (NLS) and Karyopherin beta (KPNB) from the cytoplasm to the nucleus [ 28 ]. Furthermore, KPNA5 could also mediate nuclear membrane formation, protein degradation, gene expression, cytoplasmic retention, and mRNA-related function to participate in numerous bioprocesses [ 29 ].…”

“…In many cancers, KPNA5 is highly expressed and interacts with the tumor-suppressor gene PHB2 [ 30 , 31 ]. On the other side, KPNA5 is reported to be correlated with a poor prognosis in patients with lung adenocarcinoma, and it is tightly involved in the regulation of cell cycle checkpoints and the cell mitotic cycle [ 28 ]. Along with Cdc14B, ESCO1, MAP3K3, and CSIG, KPNA5 is found to be highly expressed and regulates cell cycle and senescence progression [ 32 ].…”