SLC2A1 plays a pivotal role in cancer glycometabolism. SLC2A1 has been proposed as a putative driver gene in various cancers. However, a pan-cancer analysis of SLC2A1 has not yet been performed. In this study, we explored the expression and prognosis of SLC2A1 in pan-cancer across multiple databases. We conducted genetic alteration, epigenetic, and functional enrichment analyses of SLC2A. We calculated the correlation between SLC2A1 and tumor microenvironment using the TCGA pan-cancer dataset. We observed high expression levels of SLC2A1 with poor prognosis in most cancers. The overall genetic alteration frequency of SLC2A1 was 1.8% in pan-cancer, and the SLC2A1 promoter was hypomethylation in several cancers. Most m6A-methylation-related genes positively correlated with the expression of SLC2A1 in 33 TCGA cancers. Moreover, SLC2A1 was mainly related to the functions including epithelial–mesenchymal transition, glycolysis, hypoxia, cell-cycle regulation, and DNA repair. Finally, SLC2A1 positively associated with neutrophils and cancer-associated fibroblasts in the tumor microenvironment of most cancers and significantly correlated with TMB and MSI in various cancers. Notably, SLC2A1 was remarkably positively correlated with PD-L1 and CTLA4 in most cancers. SLC2A1 might serve as an attractive pan-cancer biomarker for providing new insights into cancer therapeutics.

Background: Long non-coding RNA (lncRNA) maternally expressed gene 3 (MEG3) has been implicated in the progression of esophageal cancer (EC). However, the specific mechanism of the involvement of MEG3 in EC development in relation to the regulation of immune escape remains uncertain. Thus, the aim of the current study was to investigate the effect of MEG3 on EC via microRNA-149-3p (miR-149-3p). Methods: Gain- and loss-of-function experiments were initially performed in EC cells in addition to the establishment of a 4-nitroquinoline 1-oxide-induced EC mouse model aimed at evaluating the respective roles of forkhead box P3 (FOXP3), MEG3, miR-149-3p, mouse double minute 2 homolog (MDM2) and p53 in T cell differentiation and immune escape observed in EC. Results: EC tissues were found to exhibit upregulated FOXP3 and MDM2 while MEG3, p53 and miR-149-3p were all downregulated. FOXP3 was confirmed to be a target gene of miR-149-3p with our data suggesting it reduced p53 ubiquitination and degradation by means of inhibiting MDM2. P53 was enriched in the promoter of miR-149-3p to upregulate miR-149-3p. The overexpression of MEG3, p53 or miR-149-3p or silencing FOXP3 was associated with a decline in CD25⁺FOXP3⁺CD4⁺ T cells, IL-10⁺CD4⁺ T cells and IL-4⁺CD4⁺ T cells in spleen tissues, IL-4, and IL-10 levels as well as C-myc, N-myc and Ki-67 expression in EC mice. Conclusion: Collectively, MEG3 decreased FOXP3 expression and resulted in repressed regulatory T cell differentiation and immune escape in EC mice by upregulating miR-149-3p via MDM2-mediated p53.

Introduction: ZC3H13 (zinc finger CCCH-type containing 13) is a member of the zinc finger protein family with regulatory roles in gene expression and represents a crucial m6A methyltransferase. However, the precise function of ZC3H13 in the esophageal squamous cell carcinoma tumor microenvironment (TME) remains incompletely understood. Our study primarily investigated the impact of ZC3H13 on m6A methylation modification in ESCC and explored the roles of ZC3H13 and M2 macrophages in ESCC.Methods: We employed bioinformatics analysis to assess the function of ZC3H13 in ESCC. Quantification of ZC3H13, CCL5, CXCL8, and macrophage infiltration in clinical samples and cell line-derived xenograft (CDX) tumor models was conducted using real-time quantitative PCR (qRT-PCR), western blot (WB), immunohistochemistry (IHC), Immunofluorescence (IF), and Enzyme-linked immunosorbent assay (ELISA). The colorimetric method was utilized to detect m6A methylation in cells and tissues. Tumor proliferation, migration, and invasion were evaluated using CCK8, EdU staining, colony formation tests, transwell assays, and CDX models.Results: We found that elevated ZC3H13 expression was positively correlated with m6A methylation modification in ESCC tumor tissue. ZC3H13 mutation led to abnormal nuclear metastasis of METTL14 and METTL3. Silencing ZC3H13 inhibited ESCC tumor growth and M2 macrophage infiltration in mice. ZC3H13 silencing also suppressed the expression of CCL5 and CXCL8 mRNA. M6A modification enhanced the stability of CXCL8 mRNA. ESCC tumors promoted the polarization of M0-M2 macrophages through the CXCL8-CXCR2 axis, which CXCR2 inhibitors or anti-CXCL8 antibodies could inhibit. Migration of M0 macrophages was facilitated by CCL5.Discussion: Our findings elucidate the connection between ZC3H13-mediated m6A modification and M2 macrophage infiltration in the ESCC-TME, resulting in M2 macrophage polarization and increased M2 macrophage infiltration.

Purpose. DNA methylation heterogeneity is a type of tumor heterogeneity in the tumor microenvironment, but studies on the identification of the molecular heterogeneity of the lung adenocarcinoma genome with respect to DNA methylation sites and their roles in lung cancer progression and prognosis are scarce. Methods. Prognosis-associated DNA methylation subtypes were filtered by the Cox proportional hazards model and then established by unsupervised cluster analysis. Association analysis of these subtypes with clinical features and functional analysis of annotated genes potentially affected by methylation sites were performed. The robustness of the model was further tested by a Bayesian network classifier. Results. Over 7 thousand methylation sites were associated with lung adenocarcinoma prognosis. We identified seven molecular methylation subtypes, including 630 methylation sites. The subtypes yielded the most stable results for differentiating methylation profiles, prognosis, and gene expression patterns. The annotated genes potentially affected by these methylation sites are enriched in biological processes such as morphogenesis and cell adhesion, but their individual impact on the tumor microenvironment and prognosis is multifaceted. Discussion. We revealed that DNA methylation heterogeneity could be clustered and associated with the clinical features and prognosis of lung adenocarcinoma, which could lead to the development of a novel molecular tool for clinical evaluation.

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