Dataset Information

Expression and Prognostic Role of PLOD1 in Malignant Glioma.

ABSTRACT:

Background

Malignant glioma is rarely curable, and factors that in?uence the prognosis of glioma patients are not fully understood. Lysyl hydroxylases such as PLOD1 promote the cross-linking in extracellular matrix (ECM) molecules, which contribute to ECM structural stability and maturation. However, the expression and prognostic role of PLOD1 in malignant glioma remained to be determined.

Methods

The expression of PLOD1 was evaluated by immunohistochemistry in 72 malignant glioma patients from Shenzhen People's hospital. The mRNA expression profiles and clinical information of malignant glioma patients were obtained from public databases, including TCGA, CGGA, Rembrandt, and Gravendeel. The correlation between gene expression and tumor grade, and IDH1/2 status and 1p19q status were evaluated. The association between gene expression and overall survival of malignant glioma patients was examined using Kaplan-Meier survival analysis. GO and KEGG pathways were analyzed by Metascape. Transwell invasion assays were performed to determine the effect of PLOD1 on migration and invasion of glioma cells in vitro.

Results

PLOD1 expression was significantly elevated in malignant glioma tissues compared with non-tumor brain tissues. Besides, elevated levels of PLOD1 were significantly correlated with high tumor grade, wildtype IDH1/2 status, and 1p19q non-codel in all the four public datasets and in-house cohort. Malignant glioma patients with high PLOD1 expression had better overall survival compared to those with low PLOD1 expression. More importantly, patients with IDH1/2 mutations, 1p19q codeletions, and PLOD1 overexpression had the best overall survival. GO enrichment pathway analysis indicated that PLOD1 participates in regulating the extracellular matrix. Transwell invasion assay, which revealed that inhibiting PLOD1 reduced cell invasion in both U87 and U251 cells.

Conclusion

PLOD1 serves as a potential prognostic marker and therapeutic target for malignant glioma.

SUBMITTER: Wang H

PROVIDER: S-EPMC7778385 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

Expression and Prognostic Role of PLOD1 in Malignant Glioma.

Wang Hao H Luo Weijian W Dai Limeng L

OncoTargets and therapy 20201229

<h4>Background</h4>Malignant glioma is rarely curable, and factors that inﬂuence the prognosis of glioma patients are not fully understood. Lysyl hydroxylases such as PLOD1 promote the cross-linking in extracellular matrix (ECM) molecules, which contribute to ECM structural stability and maturation. However, the expression and prognostic role of PLOD1 in malignant glioma remained to be determined.<h4>Methods</h4>The expression of PLOD1 was evaluated by immunohistochemistry in 72 malignant glioma ...[more]

PMID: 33402837

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Project description:IntroductionPatients with high-grade glioma (HGG) suffered poor survival due to inherent or acquired therapeutic resistance and refractory recurrence. The outcome of HGG patients has improved little during the past decade. Therefore, molecular signatures are urgently needed for improving diagnosis, survival prediction and identification of therapeutic targets for HGG. E2F transcription factors (E2Fs), a family of transcription factors recognized as master regulators of cell proliferation, have been found to be involved in the pathogenesis of various tumor types.AimsTo investigate the expression of E2Fs and their prognosis value in high-grade glioma (HGG).ResultsExpression of E2Fs was analyzed in 394 HGG samples from TCGA dataset. E2Fs were generally expressed in HGG. Except for E2F3 and E2F5, expression of E2Fs was significantly upregulated and linked with grade progression. E2F1, E2F2, E2F7, and E2F8 were highly correlated with aggressive proliferation oncogenes, as well as potential therapeutic resistance oncogenes. Elevated E2Fs (not E2F3) were associated with adverse tumor features and poorer outcome. E2F7 and E2F8 exhibited superior outcome prediction performance compared with other E2Fs. Additionally, E2F7 and E2F8 independently predicted poorer survival in HGG patients. Gene set enrichment analysis identified a variety of critical oncogenic pathways that were tightly associated with E2F7 or E2F8, including epithelial-mesenchymal transition, NFκB, STAT3, angiogenesis pathways. Furthermore, elevated expression of E2F7 indicated worse therapeutic response of HGG to irradiation and silencing of E2F7 conferred higher cell-killing effect when combined with irradiation treatment. Mechanically, E2F7 directly regulates the transcriptional activity of EZH2 via binding at the corresponding promoter area.ConclusionsE2Fs (except for E2F3 and E2F5) are highly expressed in HGG and indicate adverse outcome. E2F7 and E2F8 were identified as novel potential prognostic markers in HGG. E2F7 was further validated to be closely associated with radioresistance of HGG and a critical transcriptional regulator of EZH2.

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Project description:BackgroundCurrent treatment options for glioma are limited, and the prognosis of patients with glioma is poor as the available drugs show low therapeutic efficacy. Furthermore, the molecular mechanisms associated with glioma remain poorly understood. METTL1 mainly catalyzes the formation of N(7)-methylguanine at position 46 of the transfer RNA sequence, thereby regulating the translation process. However, the role of METTL1 in glioma has not been studied to date. The purpose of this study was to analyze the expression and prognosis of METTL1 in glioma, and to explore the potential analysis mechanism.MethodsData from five publicly available databases were used to analyze METTL1 expression across different tumor types and its differential expression between carcinoma and adjacent normal tissues. The expression of METTL1 in glioma was further validated using real-time polymerase chain reaction and immunohistochemistry. Meanwhile, siRNA was used to knockdown METTL1 in U87 glioma cells, and the resultant effect on glioma proliferation was verified using the Cell Counting Kit 8 (CCK8) assay. Furthermore, a nomogram was constructed to predict the association between METTL1 expression and the survival rate of patients with glioma.ResultsMETTL1 expression increased with increasing glioma grades and was significantly higher in glioma than in adjacent noncancerous tissues. In addition, high expression of METTL1 promoted cell proliferation. Moreover, METTL1 expression was associated with common clinical risk factors and was significantly associated with the prognosis and survival of patients with glioma. Univariate and multivariate Cox regression analyses revealed that METTL1 expression may be used as an independent prognostic risk factor for glioma. Furthermore, results of functional enrichment and pathway analyses indicate that the mechanism of METTL1 in glioma is potentially related to the MAPK signaling pathway.ConclusionsHigh METTL1 expression is significantly associated with poor prognosis of patients with glioma and may represent a valuable independent risk factor. In addition, high expression of METTL1 promotes glioma proliferation and may regulate mitogen-activated protein kinase (MAPK) signaling pathway. Thus, METTL1 may be a potential biomarker for glioma. Further investigations are warranted to explore its clinical use.

Project description:The tumor microenvironment (TME) contributes to the initiation and progression of many neoplasms. However, the impact of low-grade glioma (LGG) purity on carcinogenesis remains to be elucidated. We selected 509 LGG patients with available genomic and clinical information from the TCGA database. The percentage of tumor infiltrating immune cells and the tumor purity of LGG were evaluated using the ESTIMATE and CIBERSORT algorithms. Stromal-related genes were screened through Cox regression, and protein-protein interaction analyses and survival-related genes were selected in 487 LGG patients from GEO database. Hub genes involved in LGG purity were then identified and functionally annotated using bioinformatics analyses. Prognostic implications were validated in 100 patients from an Asian real-world cohort. Elevated tumor purity burden, immune scores, and stromal scores were significantly associated with poor outcomes and increased grade in LGG patients from the TCGA cohort. In addition, CD3E was selected with the most significant prognostic value (Hazard Ratio=1.552, P<0.001). Differentially expressed genes screened according to CD3E expression were mainly involved in stromal related activities. Additionally, significantly increased CD3E expression was found in 100 LGG samples from the validation cohort compared with adjacent normal brain tissues. High CD3E expression could serve as an independent prognostic indicator for survival of LGG patients and promotes malignant cellular biological behaviors of LGG. In conclusion, tumor purity has a considerable impact on the clinical, genomic, and biological status of LGG. CD3E, the gene for novel membrane immune biomarker deeply affecting tumor purity, may help to evaluate the prognosis and develop individual immunotherapy strategies for LGG patients. Evaluating the ratio of differential tumor purity and CD3E expression levels may provide novel insights into the complex structure of the LGG microenvironment and targeted drug development.

Dataset Information

Expression and Prognostic Role of PLOD1 in Malignant Glioma.

Background

Methods

Results

Conclusion

Publications

Expression and Prognostic Role of PLOD1 in Malignant Glioma.

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