Background: Aerobic glycolysis plays a key role in tumor metabolic reprogramming to reshape the immune microenvironment. The phosphoglycerate kinase 1 (PGK1) gene codes a glycolytic enzyme that converts 1,3-diphosphoglycerate to 3-phosphoglycerate. However, in lung adenocarcinoma (LUAD), the role of PGK1 in altering the tumor microenvironment (TME) has not yet been determined. Methods: Raw data, including bulk DNA and mRNA-seq data, methylation modification data, single-cell RNA-seq data, proteomics data, clinical case characteristics survival, immunotherapy data, and so on, were obtained from multiple independent public data sets. These data were reanalyzed to uncover the prognosis and immunological characteristics of PGK1 in LUAD. Results: We found that PGK1 mRNA and protein were considerably over-expressed in LUAD compared to normal tissue and that high PGK1 expression is associated with poorer prognostic outcomes in LUAD. The enrichment analysis of PGK1 co-expressed genes in lung adenocarcinoma revealed that PGK1 may be involved in hypoxia, metabolism, DNA synthesis, cell cycle, PI3K/AKT, and various immune and inflammatory signaling pathways. Furthermore, PGK1 is also linked to the recruitment of numerous immune cells, including aDC (dendritic cells), macrophages, and neutrophils. More importantly, PGK1 was highly expressed in immunosuppressive cells, including M2 macrophages, Tregs, and exhausted T cells, among others. Finally, higher PGK1 expression indicated significant correlations to immune checkpoints, TMB (tumor mutation burden), and high response to immunotherapy. Conclusions: The presented findings imply that PGK1, as a glycolysis core gene, may be important for the modification of the immune microenvironment by interacting with the tumor metabolism. The results of this study provide clues for a potential immunometabolic combination therapy strategy in LUAD, for which more experimental and clinical translational research is needed.

Cardiac conduction regulatory RNA (CCRR) is down‐regulated in the pathogenesis of heart failure (HF), which accordingly suppresses cardiac conduction while promoting arrhythmogenicity. Meanwhile, CX43 was reported to play a role in the pathogenesis of metastatic breast cancer and melanoma brain colonization. In this study, we studied the role of long non‐coding RNA CCRR and its interaction with CX43 in brain metastasis of breast cancer. Breast cancer patients were grouped according to the metastasis status. Real‐time PCR and IHC assay were used to measure the expression of lncRNA‐CCRR and CX43 in patients. Western blot was conducted to observe the effect of lncRNA‐CCRR on the expression of CX43 in MDA‐MB‐231BR and BT‐474BR cells. Compared with the non‐metastasis group, the mRNA expression of tissue lncRNA‐CCRR, cerebrospinal fluid (CSF) lncRNA‐CCRR, tissue CX43 and tissue protein expression of CX43 were both evidently up‐regulated in metastasis patients, especially in patients with brain metastasis. The expression of lncRNA‐CCRR was positively correlated with the up‐regulated expression of CX43. Moreover, CX43 expression was significantly lower in MDA‐MB‐231WT cells compared with that in MDA‐MB‐231BR cells. Also, the overexpression of lncRNA‐CCRR evidently increased dye transfer rate from astrocytes to MDA‐MB‐231BR/BT‐474BR cells but reduced lncRNA‐CCRR expression and suppressed the transmigration of MDA‐MB‐231BR/BT‐474BR cells in a blood‐brain barrier (BBB) model. In this study, we demonstrated that the presence of lncRNA‐CCRR could up‐regulate the expression of CX43, which promoted gap junction formation in brain metastasis of breast cancer. Accordingly, the communication between breast cancer cells and astrocytes was also promoted.

Nucleolar and spindle-associated protein 1 (NUSAP1) is a potential molecular marker and intervention target for glioblastoma (GBM). In this study, we aim to investigate upstream regulatory lncRNAs and miRNAs of NUSAP1 through both experimental and bioinformatic methods. We screened upstream lncRNAs and miRNAs of NUSAP1 through multiple databases based on ceRNA theory. Then, in vitro and in vivo experiments were performed to elucidate the relevant biological significance and regulatory mechanism among them. Finally, the potential downstream mechanism was discussed. LINC01393 and miR-128-3p were screened as upstream regulatory molecules of NUSAP1 by TCGA and ENCORI databases. The negative correlations among them were confirmed in clinical specimens. Biochemical studies revealed that overexpression or knockdown of LINC01393 respectively enhanced or inhibited malignant phenotype of GBM cells. MiR-128-3p inhibitor reversed LINC01393 knockdown-mediated impacts on GBM cells. Then, dual-luciferase reporter assay and RNA immunoprecipitation assay were conducted to validate LINC01393/miR-128-3p/NUSAP1 interactions. In vivo, LINC01393-knockdown decreased tumor growth and improved mice survival, while restoration of NUSAP1 partially reversed these effects. Additionally, enrichment analysis and western blot revealed that the roles of LINC01393 and NUSAP1 in GBM progression were associated with NF-κB activation. Our findings showed that LINC01393 sponged miR-128-3p to upregulate NUSAP1, thereby promoting GBM development and progression via activating NF-κB pathway. This work deepens understanding of GBM mechanisms and provides potential novel therapeutic targets for GBM.

Ubiquitin-Activating Enzyme E1 (UBA1), an E1 enzyme involved in the activation of ubiquitin enzymes, has been involved in the onset and progression of different cancers in humans. Nevertheless, the precise contribution of UBA1 in breast cancer (BC) is still poorly characterized. In this study, a thorough investigation was carried out to elucidate the significance of UBA1 and validate its functionality in BC. Through the analysis of mRNA sequencing data of BC patients, the mRNA expression of UBA1 was observed to be notably enhanced in cancer tissues relative to controls, and high UBA1 expression was linked to worse overall survival (OS), disease-specific survival (DSS), and progress-free survival (PFS). Moreover, UBA1 exhibited potential as an independent prognostic and diagnostic biomarker for individuals with BC. Additionally, functional enrichment analysis revealed the involvement of UBA1 in inflammation-linked pathways, like the TNF-α signaling pathway, the IL-6 signaling pathway, and various immune-related biological processes. Notably, single-sample gene set enrichment analysis (ssGSEA) aided in the identification of a negative link between UBA1 expression and the levels of infiltrating mast cells, Th1 cells, iDC cells, B cells, DC cells, Tem cells, Cytotoxic cells, T cells, CD8T cells, and pDC cells. Finally, this study demonstrated that silencing UBA1 significantly impeded the growth and development of BC cell lines. These findings highlight UBA1 as a potential prognostic biomarker linked to immune infiltration in BC, thereby depicting its potential as a new therapeutic target for individuals with BC.