Contributions and prognostic performances of m7G RNA regulators in pancreatic adenocarcinoma.
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ABSTRACT:
SUBMITTER: Yuan Q
PROVIDER: S-EPMC9746722 | biostudies-literature | 2022 Sep
REPOSITORIES: biostudies-literature
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Contributions and prognostic performances of m7G RNA regulators in pancreatic adenocarcinoma.
Yuan Qihang Q Ren Jie J Chen Xu X Dong Yantong Y Shang Dong D
Chinese medical journal 20220905 17
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Project description:BackgroundN7-methylguanosine (m7G) is present in a wide variety of organisms and has important roles. m7G has been reported to be involved in multiple biological processes, and recent studies have reported that changes in RNA modifications result in tumor cellular transformation and cancer, such as colon adenocarcinoma, lung cancer, and intrahepatic cholangiocarcinoma. However, little is known about the function of the m7G in colon adenocarcinoma.MethodsWe established two clusters based on the expression of all genes associated with m7G to explore the expression pattern of 31 key regulatory factors of m7G RNA and assess the prognostic value of regulatory factors. Wilcoxon test and differential box line plots were applied for bioinformatics analysis. Receiver Operating and Kaplan‒Meier curves were utilized to evaluate the prognostic value. Finally, four genes' expression in the colon cancer cell line was confirmed by qRT-PCR.ResultsFrom The Cancer Genome Atlas database, we found that the expression levels of 25 out of the 31 key N7-methylguanosine RNA modification regulators were significantly different in colon adenocarcinoma. According to 25 methylation regulators' expression, we identified two subgroups by consensus clustering, in which the prognosis was worse in Group 2 than in Group 1 and was significantly correlated with age. Cluster 2 was significantly enriched in tumor-associated pathways, and immune cells were highly infiltrated in Cluster 1 but weakly infiltrated in Cluster 2. Further results indicated that this risk profile may serve as a standalone predictive factor for colon adenocarcinoma, and the four genetic risk profiles' prognostic relatedness was successfully verified through Gene Expression Omnibus dataset. At last, A nomogram for prognosis was created according to age, sex, histological grading, clinicopathological staging, and hazard score to accurately predict patient prognosis in colon adenocarcinoma. We successfully validated the differential expression of four genes using qRT-PCR.ConclusionsIn the present study, we revealed the important contribution of key regulators associated with m7G RNA modifications based on all gene expression in colon adenocarcinoma and developed a signature of risk that serves as a promising prognostic marker for patients with colon adenocarcinoma.
| S-EPMC9867544 | biostudies-literature
Project description:BackgroundPancreatic cancer is poorly characterized at genetic and non-genetic levels. The current study evaluates in a large cohort of patients the prognostic relevance of molecular subtypes and key transcription factors in pancreatic ductal adenocarcinoma (PDAC).MethodsWe performed gene expression analysis of whole-tumor tissue obtained from 118 surgically resected PDAC and 13 histologically normal pancreatic tissue samples. Cox regression models were used to study the effect on survival of molecular subtypes and 16 clinicopathological prognostic factors. In order to better understand the biology of PDAC we used iRegulon to identify transcription factors (TFs) as master regulators of PDAC and its subtypes.ResultsWe confirmed the PDAssign gene signature as classifier of PDAC in molecular subtypes with prognostic relevance. We found molecular subtypes, but not clinicopathological factors, as independent predictors of survival. Regulatory network analysis predicted that HNF1A/B are among thousand TFs the top enriched master regulators of the genes expressed in the normal pancreatic tissue compared to the PDAC regulatory network. On immunohistochemistry staining of PDAC samples, we observed low expression of HNF1B in well differentiated towards no expression in poorly differentiated PDAC samples. We predicted IRF/STAT, AP-1, and ETS-family members as key transcription factors in gene signatures downstream of mutated KRAS.ConclusionsPDAC can be classified in molecular subtypes that independently predict survival. HNF1A/B seem to be good candidates as master regulators of pancreatic differentiation, which at the protein level loses its expression in malignant ductal cells of the pancreas, suggesting its putative role as tumor suppressor in pancreatic cancer.Trial registrationThe study was registered at ClinicalTrials.gov under the number NCT01116791 (May 3, 2010).
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Project description:Gliomas are the most frequent primary malignant brain tumors of the central nervous system, causing significant impairment and death. There is mounting evidence that N7 methylguanosine (m7G) RNA dysmethylation plays a significant role in the development and progression of cancer. However, the expression patterns and function of the m7G RNA methylation regulator in gliomas are yet unknown. The goal of this study was to examine the expression patterns of 31 critical regulators linked with m7G RNA methylation and their prognostic significance in gliomas. To begin, we systematically analyzed patient clinical and prognostic data and mRNA gene expression data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. We found that 17 key regulators of m7G RNA methylation showed significantly higher expression levels in gliomas. We then divided the sample into two subgroups by consensus clustering. Cluster 2 had a poorer prognosis than cluster 1 and was associated with a higher histological grade. In addition, cluster 2 was significantly enriched for cancer-related pathways. Based on this discovery, we developed a risk model involving three m7G methylation regulators. Patients were divided into high-risk and low-risk groups based on risk scores. Overall survival (OS) was significantly lower in the high-risk group than in the low-risk group. Further analysis showed that the risk score was an independent prognostic factor for gliomas.
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Project description:The diaphanous-related formin subfamily includes diaphanous homolog 1 (DIAPH1), DIAPH2, and DIAPH3. DIAPHs play a role in the regulation of actin nucleation and polymerization and in microtubule stability. DIAPH3 also regulates the assembly and bipolarity of mitotic spindles. Accumulating evidence has shown that DIAPHs are anomalously regulated during malignancy. In this study, we reviewed The Cancer Genome Atlas database and found that DIAPHs are abundantly expressed in pancreatic adenocarcinoma (PAAD). Furthermore, we analyzed the gene alteration profiles, protein expression, prognosis, and immune reactivity of DIAPHs in PAAD using data from several well-established databases. In addition, we conducted gene set enrichment analysis to investigate the potential mechanisms underlying the roles of DIAPHs in the carcinogenesis of PAAD. Finally, we performed the experimental validation of DIAPHs expression in several pancreatic cancer cell lines and tissues of patients. This study demonstrated significant correlations between DIAPHs expression and clinical prognosis, oncogenic signature gene sets, T helper 2 cell infiltration, plasmacytoid dendritic cell infiltration, myeloid-derived suppressor cell infiltration, ImmunoScore, and immune checkpoints in PAAD. These data may provide important information regarding the role and mechanisms of DIAPHs in tumorigenesis and PAAD immunotherapy.
| S-EPMC9797685 | biostudies-literature
Project description:Endoplasmic reticulum stress (ERS) and unfolded protein response are the critical processes of tumour biology. However, the roles of ERS regulatory genes in pancreatic adenocarcinoma (PAAD) remain elusive. A novel ERS-related risk signature was constructed using the Lasso regression analysis. Its prognostic value, immune effect, metabolic influence, mutational feature and therapeutic correlation were comprehensively analysed through multiple bioinformatic approaches. The biofunctions of KDELR3 and YWHAZ in pancreatic cancer (PC) cells were also investigated through colony formation, Transwell assays, flow cytometric detection and a xenograft model. The upstream miRNA regulatory mechanism of KDELR3 was predicted and validated. ERS risk score was identified as an independent prognostic factor and could improve traditional prognostic model. Meanwhile, it was closely associated with metabolic reprogramming and tumour immune. High ERS risk enhanced glycolysis process and nucleotide metabolism, but was unfavourable for anti-tumour immune response. Moreover, ERS risk score could act as a potential biomarker for predicting the efficacy of ICBs. Overexpression of KDELR3 and YWHAZ stimulated the proliferation, migration and invasion of SW1990 and BxPC-3 cells. Silencing KDELR3 suppressed tumour growth in a xenograft model. miR-137 could weaken the malignant potentials of PC cells through inhibiting KDELR3 (5'-AGCAAUAA-3'). ERS risk score greatly contributed to PAAD clinical assessment. KDELR3 and YWHAZ possessed cancer-promoting capacities, showing promise as a novel treatment target.
| S-EPMC10902308 | biostudies-literature
Project description:N6-methyladenosine (m6A) RNA modification is the most abundant modification method in mRNA, and it plays an important role in the occurrence and development of many cancers. This paper mainly discusses the role of m6A RNA methylation regulators in lung adenocarcinoma (LUAD) to identify novel prognostic biomarkers. The gene expression data of 19 m6A methylation regulators in LUAD patients and its relevant clinical parameters were extracted from The Cancer Genome Atlas (TCGA) database. We selected three significantly differentially expressed m6A regulators in LUAD to construct the risk signature, and evaluated its prognostic prediction efficiency using the receiver operating characteristic (ROC) curve. Kaplan-Meier survival analysis and Cox regression analysis were used to identify the independent prognostic significance of the risk signature. The ROC curve indicated that the area under the curve (AUC) was 0.659, which means that the risk signature had a good prediction efficiency. The results of the Kaplan-Meier survival analysis and Cox regression analysis showed that the risk score can be used as an independent prognostic factor for LUAD. In addition, we explored the differential signaling pathways and cellular processes related to m6A methylation regulators in LUAD.
| S-EPMC8306618 | biostudies-literature
Project description:Chronic obstructive pulmonary disease (COPD) is one of the most common lung injury diseases, closely associated with aging, air pollution and smoking exposure. The novel epigenetic modification 7-methylguanosine (m7G) RNA methylation affects the pathogenesis and progression of COPD. In this study, the combined roles of m7G methylation regulators were explored in COPD for the first time by integrated bioinformatic methods. The machine algorithms screened 7 disease signature genes relevant to clinical indicators, including CYFIP2, EIF3D, EIF4G3, GEMIN5, METTL1, SNUPN and NCBP2, and METTL1 was related to the progression in COPD. COPD patients could be well divided into two m7G subtypes by consensus clustering, and the two groups had differential immune profiles, visualized by single-cell sequencing and immune infiltration landscapes. More importantly, CAT was found to be a meaningful key target gene in METTL1-CAT axis for m7G methylation in COPD. We also used the cell premature senescence model for the preliminary validation of the above biosignature analysis results. The qRT-PCR and GSEA results revealed the important regulatory roles of the seven disease signature genes in COPD and aging-related diseases. Taken together, METTL1 and its target CAT have played an important role in COPD, as excellent candidates for its prevention and intervention.
| S-EPMC11926379 | biostudies-literature
Project description:To evaluate the prognostic relevance of molecular subtypes and key transcription factors in pancreatic ductal adenocarcinoma (PDAC), we performed gene expression analysis of whole-tumor tissue obtained from 118 surgically resected PDAC and 13 control samples.
2016-08-17 | GSE62165 | GEO
Project description:Background: 7-Methylguanosine (m7G) is an important posttranscriptional modification that regulates gene expression and is involved in tumorigenesis and development. Tumor microenvironment has been proven to be highly involved in tumor progression and prognosis. However, how m7G-associated genes affect the tumor microenvironment of patients with lung adenocarcinoma (LUAD) remains to be further clarified. Methods: The genetic alterations of m7G-associated genes and their associations with the prognosis and tumor microenvironment in LUAD patients were systemically analyzed. An m7G-Riskscore was established and analyzed for its performance in disease prognosis and association with patient response to immunotherapy. Expression of the model genes at the protein level was investigated through ex vivo experiments. A nomogram was finally obtained based on the m7G-Riskscore and several significant clinical pathological features. Results: m7G-Associated genes were obtained from five LUAD datasets from The Cancer Genome Atlas and Gene Expression Omnibus databases, and their expression pattern was determined. Based on the m7G-associated genes, three LUAD clusters were defined. The differentially expressed genes from the three clusters were screened and used to further divide the LUAD patients into two gene clusters. It was demonstrated that the alterations of m7G-associated genes were associated with the clinical pathological features, prognosis, and tumor immune infiltration in LUAD patients. An m7G-Riskscore including CAND1, RRM2, and SLC2A1 was obtained with robust and accurate prognostic performance. WB and cell immunofluorescence also showed significant dysregulation of CAND1, RRM2, and SLC2A1 in LUAD. In addition, a nomogram was established to improve the clinical feasibility of the m7G-Riskscore. Correlation analysis revealed that patients with a lower m7G-Riskscore had higher immune and stromal scores, responded well to chemotherapeutics and multiple targeted drugs, and survived longer. Patients with a higher m7G-Riskscore tended to suffer from a higher tumor mutation burden. Furthermore, the m7G-Riskscore exhibited significant associations with immune cell infiltration and cancer stemness. Conclusion: This study systemically analyzed m7G-associated genes and identified their potential role in tumor microenvironment and prognosis in patients with LUAD. The findings of the present study may help better understand LUAD from the m7G perspective and also provide a new thought toward the prognosis and treatment of LUAD.
| S-EPMC9422053 | biostudies-literature
Project description:ObjectivesThe expression profiles, biological mechanisms, and clinical relevance of m7G regulators in glioma were studied in this research.MethodsBased on the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) datasets, glioma patients, can be categorized into three groups according to 29 m7G regulators, and different subtypes of glioma show different immune cell infiltration characteristics, function enrichment, and clinical prognosis. Three gene clusters were confirmed by utilizing the differentially expressed genes (DEGs) across the three m7G clusters.ResultsA prognostic signature based on 12 m7G regulators was established and validated, producing an effective tool for predicting overall survival (OS) in glioma patients. High m7G scores indicated elevated tumor mutation burden and activation of immunity, suggesting an inflamed tumor microenvironment phenotype with poor overall survival. Low m7G scores characterized by a lack of immune infiltration and low mutation burden indicated a non-inflamed phenotype with a favorable clinical prognosis. It was also found that the m7G risk scores can affect chemotherapy sensitivity and prognosis of patients who received immunotherapy. The hub gene EIF4E1B of m7G regulators can inhibit the in vitro progression of glioma cells by regulating PD-L1 expression through p53 signaling pathway-related inactivation.ConclusionsThe m7G prognostic signature can be a biomarker of the overall survival of patients with glioma. An initial in-vitro experiment suggested the potential biological mechanisms of immune regulation, with m7G regulators affecting glioma progression by modulating immune responses. The present research provides a better understanding of how m7G regulators function in glioma progression as well as the impact on clinical outcomes, which can provide new insights that might be beneficial for precision therapy of glioma.
| S-EPMC9908444 | biostudies-literature