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Stromal protein CCN family contributes to the poor prognosis in lower-grade gioma by modulating immunity, matrix, stemness, and metabolism.

ABSTRACT: Background: The CCN family of stromal proteins is involved in the regulation of many important biological functions. However, the role of dysregulated CCN proteins in lower-grade glioma (LGG) remain less understand. Methods: The clinical significance of the CCN proteins was explored based on RNA-seq profiles from multiple cohorts. A CCNScore was constructed using LASSO regression analysis. The PanCanAtlas data and MEXPRESS database were employed to elucidate molecular underpinnings. Results: The expression of CCN4 was associated with poor prognosis in LGG. The CCNScore (CCN1 = 0.06, CCN4 = 0.86) showed implication in prognosis prediction, subtype assessment and therapy selection. The gene mutation pattern of the high-CCNScore group was similar with glioblastoma, including EGFR, PTEN, and NF1 mutation frequently. Besides, the high-CCNScore group was comprised of samples mainly classic-like and mesenchymal-like, had lower methylation levels, higher stemness, higher inflammation, higher levels of extracellular matrix remodel and dysfunction of metabolic pathways. On the other hand, the low-CCNScore group consisted mainly of IDH-mutation LGG, and was characterized by TP53, CIC, and ATRX gene mutations, hyper-methylation status, lower stemness, lower proliferation, immune quietness and low extracellular matrix stiffness. Conclusion: In summary, these results outlined the role of CCN family in LGG and provided a potential and promising therapeutic target.

SUBMITTER: Liu Z

PROVIDER: S-EPMC9800986 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Stromal protein CCN family contributes to the poor prognosis in lower-grade gioma by modulating immunity, matrix, stemness, and metabolism.

Liu Zhihui Z Wu Jiasheng J Ji Hang H Zhao Hongtao H Wang Fang F Dong Jiawei J Zhang Jiheng J Wang Nan N Yan Xiuwei X Wang Kaikai K Hu Shaoshan S

Frontiers in molecular biosciences 20221216

<b>Background:</b> The CCN family of stromal proteins is involved in the regulation of many important biological functions. However, the role of dysregulated CCN proteins in lower-grade glioma (LGG) remain less understand. <b>Methods:</b> The clinical significance of the CCN proteins was explored based on RNA-seq profiles from multiple cohorts. A CCNScore was constructed using LASSO regression analysis. The PanCanAtlas data and MEXPRESS database were employed to elucidate molecular underpinnings ...[more]

PMID: 36589241

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Project description:ObjectiveAs a prevalent and infiltrative cancer type of the central nervous system, the prognosis of lower-grade glioma (LGG) in adults is highly heterogeneous. Recent evidence has demonstrated the prognostic value of the mRNA expression-based stemness index (mRNAsi) in LGG. Our aim was to develop a stemness index-based signature (SI-signature) for risk stratification and survival prediction.MethodsDifferentially expressed genes (DEGs) between LGG in the Cancer Genome Atlas (TCGA) and normal brain tissue samples from the Genotype-Tissue Expression (GTEx) project were screened out, and the weighted gene correlation network analysis (WGCNA) was employed to identify the mRNAsi-related gene sets. Meanwhile, the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed for the functional annotation of the key genes. ESTIMATE was used to calculate tumor purity for acquiring the correct mRNAsi. Differences in overall survival (OS) between the high and low mRNAsi (corrected mRNAsi) groups were compared using the Kaplan Meier analysis. By combining the Lasso regression with univariate and multivariate Cox regression, the SI-signature was constructed and validated using the Chinese Glioma Genome Atlas (CGGA).ResultsThere was a significant difference in OS between the high and low mRNAsi groups, which was also observed in the two corrected mRNAsi groups. Based on threshold limits, 86 DEGs were most significantly associated with mRNAsi via WGCNA. Seven genes (ADAP2, ALOX5AP, APOBEC3C, FCGRT, GNG5, LRRC25, and SP100) were selected to establish a risk signature for primary LGG. The ROC curves showed a fair performance in survival prediction in both the TCGA and the CGGA validation cohorts. Univariate and multivariate Cox regression revealed that the risk group was an independent prognostic factor in primary LGG. The nomogram was developed based on clinical parameters integrated with the risk signature, and its accuracy for predicting 3- and 5-years survival was assessed by the concordance index, the area under the curve of the time-dependent receiver operating characteristics curve, and calibration curves.ConclusionThe SI-signature with seven genes could serve as an independent predictor, and suggests the importance of stemness features in risk stratification and survival prediction in primary LGG.

Dataset Information

Stromal protein CCN family contributes to the poor prognosis in lower-grade gioma by modulating immunity, matrix, stemness, and metabolism.

Publications

Stromal protein CCN family contributes to the poor prognosis in lower-grade gioma by modulating immunity, matrix, stemness, and metabolism.

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