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A three-molecule score based on Notch pathway predicts poor prognosis in non-metastasis clear cell renal cell carcinoma.

ABSTRACT: We constructed a three-molecule score based on the expression of Notch pathway molecules: Jagged1, intracellular Notch1 (ICN1) and Hes1 (JIH score). To assess prognostic value of the JIH score in non-metastasis clear cell renal cell carcinoma (ccRCC), we identified 467 patients who underwent nephrectomy during 2008-2009 as our study population. Immunohistochemistry was used to evaluate the expression of these three molecules. Cox regression models were applied to construct the JIH score, while Kaplan-Meier methods, multivariate analyses and nomogram were used to explore prognostic value of the JIH score. Our result confirmed that JIH score was an independent prognosticator for both overall survival (OS) and recurrence-free survival (RFS). Survival analyses showed that a higher JIH score indicated worse clinical outcomes (JIH score 3: 58.3% and 58.0% for 6-year OS and RFS, respectively; JIH score 0: 96.7% and 91.6% for 6-year OS and RFS, respectively). Nomograms based on JIH score and other conventional clinicopathological features had a better capability in predicting patients with pT1 stage disease for both OS and RFS (84.6% and 83.9%, respectively). The JIH score is a novel prognosticator representing activation of Notch pathway for non-metastasis ccRCC, and raises an alternative strategy for excavating potential biomarkers for signal pathways.

SUBMITTER: Liu Z

PROVIDER: S-EPMC5356573 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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A three-molecule score based on Notch pathway predicts poor prognosis in non-metastasis clear cell renal cell carcinoma.

Liu Zheng Z Fu Qiang Q Fu Hangcheng H Wang Zewei Z Xu Le L An Huimin H Li Yanfeng Y Xu Jiejie J

Oncotarget 20161001 42

We constructed a three-molecule score based on the expression of Notch pathway molecules: Jagged1, intracellular Notch1 (ICN1) and Hes1 (JIH score). To assess prognostic value of the JIH score in non-metastasis clear cell renal cell carcinoma (ccRCC), we identified 467 patients who underwent nephrectomy during 2008-2009 as our study population. Immunohistochemistry was used to evaluate the expression of these three molecules. Cox regression models were applied to construct the JIH score, while K ...[more]

PMID: 27612417

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Project description:BackgroundRunt-related transcription factor 1 (RUNX1) was previously reported to play a dual role in promoting or suppressing tumorigenesis in various malignancies. A public dataset from The Cancer Genome Atlas (TCGA) was used to evaluate the role of RUNX1 in clear cell renal cell carcinoma (ccRCC).MethodsThe Wilcoxon signed-rank test was used to compare the expression of RUNX1 in ccRCC tissues and normal tissues. The Wilcoxon signed-rank test and logistic regression were utilized to investigate the relationship between clinicopathological factors and RUNX1 expression. Additionally, we analysed the differences in prognosis between patients with high and low expression of RUNX1 via the Kaplan-Meier method and Cox regression. Gene set enrichment analysis (GSEA) was performed to explore the mechanisms of RUNX1 in ccRCC.ResultsThe expression of RUNX1 in ccRCC tissues was significantly higher than that in normal tissues. High expression of RUNX1 was significantly associated with gender (p = 0.003), clinical stage (p < 0.001), tissue infiltration (p < 0.001), lymph node metastasis (p = 0.037) and histological grade (p < 0.001). Logistic regression analysis showed that high RUNX1 expression was significantly correlated with gender (OR = 1.71 for male vs. female, p = 0.004), histological grade (OR = 11.61 for grade IV vs. I, p < 0.001), clinical stage (OR = 1.55 for stage III/IV vs. I/II, p = 0.014) and tissue infiltration (OR = 1.54 for positive vs. negative, p = 0.018). Kaplan-Meier survival curves revealed that the prognosis of patients with ccRCC with high RUNX1 expression was worse than that of patients with ccRCC with low RUNX1 expression (p < 0.001). Univariate Cox regression analysis showed that high RUNX1 expression was strongly correlated with poor prognosis (HR = 1.60, 95% CI [1.31-1.97], p < 0.001). In addition, high expression of RUNX1 was an independent prognostic factor for poor overall survival (OS), with an HR of 1.50 (95% CI [1.20-1.87], p < 0.001) in multivariate Cox analysis. GSEA showed that the apoptosis, B cell receptor signalling pathway, calcium signalling pathway, chemokine signalling pathway, JAK/STAT signalling pathway, MAPK signalling pathway, p53 signalling pathway, pathways in cancer, T cell receptor signalling pathway, Toll-like receptor signalling pathway, VEGF signalling pathway, and Wnt signalling pathway were significantly enriched in the RUNX1 high-expression phenotype. In conclusion, RUNX1 can be used as a novel prognostic factor and therapeutic target in ccRCC.

Project description:BackgroundPrevious reports have shown that short/branched chain acyl-CoA dehydrogenase (ACADSB) plays an important role in glioma, but its role in clear cell renal carcinoma (ccRCC) has not been reported.MethodsThe TIMER and UALCAN databases were used for pan-cancer analysis. RNA sequencing and microarray data of patients with ccRCC were downloaded from the Cancer Genome Atlas and Gene Expression Omnibus database. The differential expression of ACADSB in ccRCC and normal kidney tissues was tested. Correlations between ACADSB expression and clinicopathological parameters were assessed using the Wilcoxon test. The influences of ACADSB expression and clinicopathological parameters on overall survival were assessed using Cox proportional hazards models. Gene set enrichment analysis (GSEA) was performed to explore the associated gene sets enriched in different ACADSB expression phenotypes. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on genes with similar expression patterns to ACADSB. Correlations between ACADSB and ferroptosis-related genes were assessed using Spearman's correlation analysis.ResultsPan-cancer analysis revealed that ACADSB is down-regulated in multiple cancers, and decreased expression of ACADSB correlates with poor prognosis in certain types of cancer. Differential expression analyses revealed that ACADSB was down-regulated in ccRCC, indicating that ACADSB expression could be a single significant parameter to discriminate between normal and tumor tissues. Clinical association analysis indicated that decreased ACADSB expression was associated with high tumor stage and grade. The Cox regression model indicated that low ACADSB expression was an independent risk factor for the overall survival of patients with ccRCC. GSEA showed that 10 gene sets, including fatty acid (FA) metabolism, were differentially enriched in the ACADSB high expression phenotype. GO and KEGG pathway enrichment analysis revealed that ACADSB-related genes were significantly enriched in categories related to FA metabolism, branched-chain amino acid (BCAA) metabolism, and iron regulation. Spearman's correlation analysis suggested that the expression of ACADSB was positively correlated with the expression of ferroptosis driver genes.ConclusionsACADSB showed good diagnostic and prognostic abilities for ccRCC. The downregulation of ACADSB might promote tumorigenesis and tumor progression by inhibiting FA catabolism, BCAA catabolism, and ferroptosis in ccRCC.

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A three-molecule score based on Notch pathway predicts poor prognosis in non-metastasis clear cell renal cell carcinoma.

Publications

A three-molecule score based on Notch pathway predicts poor prognosis in non-metastasis clear cell renal cell carcinoma.

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