Dataset Information

Bioinformatics and survival analysis of glia maturation factor-γ in pan-cancers.

ABSTRACT:

Background

Glia maturation factor-γ (GMFG) is reported to inhibit the actin nucleation through binding to the actin-related protein-2/3 complex (Arp2/3). Considering the main function of GMFG in actin remodeling, which is vital for immune response, angiogenesis, cell division and motility, GMFG is supposed to have important roles in tumor development, while up to now, only two studies described the role of GMFG in cancers. By investigating the clinical values of GMFG using The Cancer Genome Atlas (TCGA) data and the functional mechanisms of GMFG through analyses of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichments, this study was aimed to better understand the impact of GMFG in pan-cancers and to draw more attentions for the future research of GMFG.

Methods

RNA-seq and clinical data of cancer patients were collected from TCGA and analyzed by the Kaplan-Meier methods. GO and KEGG analyses were conducted using the online tools from the Database for Annotation, Visualization and Integrated Discovery (DAVID).

Results

Compared to the corresponding normal samples, GMFG was significantly upregulated in glioblastoma (GBM), kidney clear cell carcinoma (KIRC), lower grade glioma (LGG), acute myeloid leukemia (LAML), and pancreatic cancer (PAAD), testicular cancer (TGCT), but was downregulated in kidney chromophobe (KICH), lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) (P < 0.05 for all). High expression of GMFG predicted worse OS in GBM (HR = 1.5, P = 0.017), LGG (HR = 2.2, P < 0.001), LUSC (HR = 1.4, P = 0.022) and ocular melanomas (UVM) (HR = 7, P < 0.001), as well as worse DFS in LGG (HR = 1.8, P < 0.001) and prostate cancer (PRAD) (HR = 1.9, P = 0.004). In contrast, high expression of GMFG was associated with better OS in skin cutaneous melanoma (SKCM) (HR = 0.59, P < 0.001) and thymoma (THYM) (HR = 0.098, P = 0.031), as well as better DFS in bile duct cancer (CHOL) (HR = 0.2, P = 0.003). GMFG was mainly involved in the immune response, protein binding and cytokine-cytokine receptor interaction pathways, and was positively associated with multiple immunomodulators in most cancers.

Conclusion

Our study preliminarily identified that GMFG may cause different survivals for different cancers through modulating tumor progression, immune response status and tissue-specific tumor microenvironment (TME).

SUBMITTER: Lan A

PROVIDER: S-EPMC8052856 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundGlia maturation factor-γ (GMFG) regulates actin cytoskeletal organization and promotes the invasion of cancer cells. However, its expression pattern and molecular function in gliomas have not been clearly defined.MethodsIn this study, public datasets comprising 2,518 gliomas samples were used to explore GMFG expression and its correlation with malignancy in gliomas. Immunohistochemistry (IHC) staining was performed to determine the expression of GMFG in gliomas using an in-house cohort that contained 120 gliomas samples. Gene ontology enrichment analysis was conducted using the DAVID tool. The correlation between GMFG expression and immune cell infiltration was evaluated using TIMER, Tumor Immune Single-Cell Hub (TISCH) database, and IHC staining assays. The Kaplan-Meier analysis was performed to determine the prognostic role of GMFG and its association with temozolomide (TMZ) response in gliomas.ResultsThe GMFG expression was higher in gliomas compared with non-tumor brain tissues both in public datasets and in-house cohort. High expression of GMFG was significantly associated with WHO grade IV, IDH 1/2 wild-type, and mesenchymal (ME) subtypes. Bioinformatic prediction and IHC analysis revealed that GMFG expression obviously correlated with the macrophage marker CD163 in gliomas. Moreover, both lower grade glioma (LGG) and glioblastoma multiforme (GBM) patients with high GMFG expression had shorter overall survival than those with low GMFG expression. These results indicate that GMFG may be a therapeutic target for the treatment of such patients. Patients with low GMFG expression who received chemotherapy had a longer survival time than those with high GMFG expression. For patients who received ion radiotherapy (IR) only, the GMFG expression level had no effect on the overall survival neither in CGGA and TCGA datasets.ConclusionThe GMFG is a novel prognostic biomarker for patients with both LGG and GBM. Increased GMFG expression is associated with tumor-associated macrophages (TAMs) infiltration and with a bad response to TMZ treatment.

Project description:Monocyte migration requires the dynamic redistribution of integrins through a regulated endo-exocytosis cycle, but the complex molecular mechanisms underlying this process have not been fully elucidated. Glia maturation factor-γ (GMFG), a novel regulator of the Arp2/3 complex, has been shown to regulate directional migration of neutrophils and T-lymphocytes. In this study, we explored the important role of GMFG in monocyte chemotaxis, adhesion, and β1-integrin turnover. We found that knockdown of GMFG in monocytes resulted in impaired chemotactic migration toward formyl-Met-Leu-Phe (fMLP) and stromal cell-derived factor 1α (SDF-1α) as well as decreased α5β1-integrin-mediated chemoattractant-stimulated adhesion. These GMFG knockdown impaired effects could be reversed by cotransfection of GFP-tagged full-length GMFG. GMFG knockdown cells reduced the cell surface and total protein levels of α5β1-integrin and increased its degradation. Importantly, we demonstrate that GMFG mediates the ubiquitination of β1-integrin through knockdown or overexpression of GMFG. Moreover, GMFG knockdown retarded the efficient recycling of β1-integrin back to the plasma membrane following normal endocytosis of α5β1-integrin, suggesting that the involvement of GMFG in maintaining α5β1-integrin stability may occur in part by preventing ubiquitin-mediated degradation and promoting β1-integrin recycling. Furthermore, we observed that GMFG interacted with syntaxin 4 (STX4) and syntaxin-binding protein 4 (STXBP4); however, only knockdown of STXBP4, but not STX4, reduced monocyte migration and decreased β1-integrin cell surface expression. Knockdown of STXBP4 also substantially inhibited β1-integrin recycling in human monocytes. These results indicate that the effects of GMFG on monocyte migration and adhesion probably occur through preventing ubiquitin-mediated proteasome degradation of α5β1-integrin and facilitating effective β1-integrin recycling back to the plasma membrane.

Project description:BackgroundAlthough branched chain amino acid transaminase 1 (BCAT1) has been identified to play an essential role in multiple tumors, no studies on its role in pan-cancer have been consulted before.MethodsThe study comprehensively analyzes the expression, potential mechanisms, and clinical significance of BCAT1 in pan-cancer through utilizing 16,847 samples, providing novel clues for the treatment of cancers. A Kruskal-Wallis test and the Wilcoxon rank-sum and signed-rank tests were applied to investigate diverse BCAT1 expression between various groups (e.g., cancer tissues versus normal tissues). Spearman's rank correlation coefficient was used in all correlation analyses in the study. Cox analyses and Kaplan-Meier curves were utilized to identify the prognosis significance of BCAT1 expression in cancers. The significance of BCAT1 expression in differentiating cancer and non-cancer tissues was explored via the area under the receiver operating characteristic curves (AUC).ResultsThe differential expression of BCAT1 was detected in various cancers (p < 0.05), which is relevant to some DNA methyltransferases expression. BCAT1 expression was associated with mismatch repair gene expression, immune checkpoint inhibitors expression, microsatellite instability, and tumor mutational burden in some cancers, indicating its potential in immunotherapy. BCAT1 expression showed prognosis significance and played a risk role in multiple cancers (hazard ratio > 0, p < 0.05). BCAT1 expression also demonstrated conspicuous ability to distinguish some cancers tissues from their normal tissues (AUC > 0.7), indicating its potential to detect cancers. Further analyses on head and neck squamous cell carcinoma certified upregulated BCAT1 expression at both mRNA and protein levels in this disease based on in-house tissue microarrays and multicenter datasets.ConclusionsFor the first time, the research comprehensively demonstrates the overexpression of BCAT1 in pan-cancer, which improves the understanding of the pathogenesis of BCAT1 in pan-cancer. Upregulated BCAT1 expression represented a poor prognosis for cancers patients, and it serves as a potential marker for cancer immunotherapy.

Project description:BackgroundHepatic leukemia factor (HLF) is associated with cancer onset, growth, and progression; however, little is known regarding its biological role in pan-cancer. In order to further evaluate the diagnostic and prognostic value of HLF in pan-cancer and colorectal cancer (CRC), we performed comprehensive bioinformatics analyses of the molecular mechanism of HLF in pan-cancer, with subsequent verification in CRC.MethodsWe downloaded data (gene expression, clinical data, follow-up duration, and immune-related data) related to 33 solid tumor types from UCSC Xena (University of California Santa Cruz cancer database, https://xena.ucsc.edu/). HLF expression was analyzed in pan-cancer, and its diagnostic efficacy, prognostic value, and correlation with pathological stage and cancer immunity were determined. We also analyzed gene alterations in HLF and biological processes involved in its regulation in pan-cancer. Using CRC data in The Cancer Genome Atlas (TCGA), we assessed correlations between HLF and CRC diagnosis, prognosis, and drug sensitivity and performed functional enrichment analyses. Moreover, we constructed an HLF-related ceRNA regulatory network. Finally, we externally validated HLF expression and diagnostic and prognostic value in CRC using Gene Expression Omnibus (GEO) database, as well as by performing in vitro experiments.ResultsHLF expression was downregulated in most tumors, and HLF showed good predictive potential for pan-cancer diagnosis and prognosis. It was closely related to the clinicopathological stages of pan-cancer. Further, HLF was associated with tumor microenvironment and immune cell infiltration in many tumors. Analyses involving cBioPortal revealed changes in HLF amplifications and mutations in most tumors. HLF was also closely associated with microsatellite instability and tumor mutational burden in pan-cancer and involved in regulating various tumor-related pathways and biological processes. In CRC, HLF expression was similarly downregulated, with implications for CRC diagnosis and prognosis. Functional enrichment analysis indicated the association of HLF with many cancer-related pathways. Further, HLF was associated with drug (e.g., oxaliplatin) sensitivity in CRC. The ceRNA regulatory network showed multigene regulation of HLF in CRC. External validation involving GEO databases and quantitative real-time polymerase chain reaction (qRT-PCR) data substantiated these findings.ConclusionsHLF expression generally exhibited downregulation in pan-cancer, contributing to tumor occurrence and development by regulating various biological processes and affecting tumor immune characteristics. HLF was also closely related to CRC occurrence and development. We believe HLF can serve as a reliable diagnostic, prognostic, and immune biomarker for pan-cancer.