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High Expression of ERK-related RASGRF2 predicts Poor prognosis in patients with Stomach Adenocarcinoma and correlates with M2 macrophage

ABSTRACT: Background: The role of RASGRF2 has been verified in the development of various cancers. However, its roles in stomach adenocarcinoma (STAD) are still under investigation. Methods: RASGRF2 transcript-level data and the associated clinical information from patients with STAD were extracted from The Cancer Genome Atlas (TCGA). Diagnostic and prognostic values of RASGRF2 were analyzed using receiver-operator characteristics (ROC) analysis, correlation analysis, and survival analysis in conjunction with a prognostic model. In addition, gene expression profiles, differentially-expressed genes for co-varying expression, and a differential expressed genes (DEG) protein-protein interaction network for influential nodes were also analyzed. To identify the molecular role of RASGRF2 in STAD, gene ontology (GO) term, Kyoto Encyclopedia of Genes and Genomes (KEGG) biological pathway, and gene set enrichment analysis (GSEA)-mediated functional module enrichment analyses were conducted. The relationship between RASGRF2 and gene signature-based predicted immune cell infiltration patterns were also investigated. To validate the bioinformatic findings, RASGRF2 protein expression was investigated in vitro using western blot and immunohistochemistry. Furthermore, relationships among RASGRF2 protein expression, clinicopathologic characteristics, and patient survival were analyzed. Results: Bioinformatic analysis revealed a significantly higher RASGRF2 transcript level in STAD tissue, which was positively associated with the T stage, histological type, histological grade, and TP53 status. Moreover, the RASGRF2 transcript level indicated poor overall survival in STAD patients (hazard ratio = 1.47, P = 0.023). Multivariate Cox regression analysis showed that primary therapy outcome, age, and RASGRF2 transcript level were independent prognostic factors for survival, and the C-index of a nomogram was 0.695. Additionally, 159 genes were differentially expressed according to RASGRF2 transcript levels; 15 exhibited co-varying expression, and 13 were identified as influential nodes. The DEG-list was significantly enriched for several GO terms, biological pathways, and functional modules, including MAPK, RAS, ERK, and immunoregulatory pathways. RASGRF2 transcript levels were significantly positively correlated with infiltration levels of Tem, Macrophages, pDCs, and NK cells. Validation analysis showed similar results for the RASGRF2 protein expression level in both in vitro analyses. Conclusion: Bioinformatic predictions combined with in vitro validation suggest that RASGRF2 plays diagnostic and prognostic roles and serves as a negative protective molecular factor in STAD patients.

SUBMITTER: Du Y

PROVIDER: S-EPMC8558656 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundGlucosamine 6-phosphate N-acetyltransferase (GNPNAT1) is a key enzyme in the hexosamine biosynthetic pathway (HBP), which functions as promoting proliferation in some tumors, yet its potential biological function and mechanism in lung adenocarcinoma (LUAD) have not been explored.MethodsThe mRNA differential expression of GNPNAT1 in LUAD and normal tissues was analyzed using the Cancer Genome Atlas (TCGA) database and validated by real-time PCR. The clinical value of GNPNAT1 in LUAD was investigated based on the data from the TCGA database. Then, immunohistochemistry (IHC) of GNPNAT1 was applied to verify the expression and clinical significance in LUAD from the protein level. The relationship between GNPNAT1 and epigenetics was explored using the cBioPortal database, and the miRNAs regulating GNPNAT1 were found using the miRNA database. The association between GNPNAT1 expression and tumor-infiltrating immune cells in LUAD was observed through the Tumor IMmune Estimation Resource (TIMER). Finally, Gene set enrichment analysis (GSEA) was used to explore the biological signaling pathways involved in GNPNAT1 in LUAD.ResultsGNPNAT1 was upregulated in LUAD compared with normal tissues, which was verified through qRT-PCR in different cell lines (P < 0.05), and associated with patients' clinical stage, tumor size, and lymphatic metastasis status (all P < 0.01). Kaplan-Meier (KM) analysis suggested that patients with upregulated GNPNAT1 had a relatively poor prognosis (P < 0.0001). Furthermore, multivariate Cox regression analysis indicated that GNPNAT1 was an independent prognostic factor for LUAD (OS, TCGA dataset: HR = 1.028, 95% CI: 1.013-1.044, P < 0.001; OS, validation set: HR = 1.313, 95% CI: 1.130-1.526, P < 0.001). GNPNAT1 overexpression was correlated with DNA copy amplification (P < 0.0001), low DNA methylation (R = -0.52, P < 0.0001), and downregulation of hsa-miR-30d-3p (R = -0.17, P < 0.001). GNPNAT1 expression was linked to B cells (R = -0.304, P < 0.0001), CD4+T cells (R = -0.218, P < 0.0001), and dendritic cells (R = -0.137, P = 0.002). Eventually, GSEA showed that the signaling pathways of the cell cycle, ubiquitin-mediated proteolysis, mismatch repair and p53 were enriched in the GNPNAT1 overexpression group.ConclusionGNPNAT1 may be a potential prognostic biomarker and novel target for intervention in LUAD.

Project description:BackgroundInterleukin 6 (IL6) is both a pleiotropic cytokine and an immune-related gene. Interleukin 6 receptor (IL6R) is the receptor for IL6. It may be closely connected to the development of lung cancer. This research aims to explore the prognostic value of IL6R and prevent overtreatment of patients with lung adenocarcinoma (LUAD).MethodsIn this study, the expression of IL6R in tumor tissues and surrounding tissues was first analyzed by immunohistochemistry in the Affiliated Hospital of Nantong University (NTU) cohort. Secondly, we downloaded information from The Cancer Genome Atlas (TCGA) for the TCGA cohort and used this information to explore the messenger RNA (mRNA) level of IL6R. We then used Kaplan-Meier survival analyses, univariate and multivariate Cox analyses, nomogram models, and decision curve analyses to assess the prognostic value of IL6R. In addition, we also analyzed immune cell infiltration and the signaling pathways related to IL6R through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA).ResultsThrough the data analysis of the NTU cohort and the TCGA cohort, it was found that the expression of IL6R in normal tissues around the tumor was higher than that in tumor tissue, and was positively correlated with the overall survival (OS) of LUAD patients. Additionally, low expression of IL6R was found to be an independent predictor of poor prognosis among the patients in these two research cohorts. Next, using GO, KEGG, and GSEA analyses, we found that partially infiltrated tumor immune cells might be related to earlier staging and better prognosis of patients with LUAD. Finally, the study of the 3-5-year survival rate of LUAD patients through the nomogram showed that the expression of IL6R could improve the accuracy of prediction to prevent the overtreatment of some LUAD patients.ConclusionsIn summary, our study indicated that the low expression of IL6R was associated with poor prognosis among LUAD patients and that low expression of IL6R is a potential independent risk factor that could provide a basis for strengthening postoperative classification management of such patients.

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High Expression of ERK-related RASGRF2 predicts Poor prognosis in patients with Stomach Adenocarcinoma and correlates with M2 macrophage

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