Expression of AOX1 Predicts Prognosis of Clear Cell Renal Cell Carcinoma.
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ABSTRACT:
SUBMITTER: Xiong L
PROVIDER: S-EPMC8287305 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Disruptor of telomeric silencing 1-like (Dot1l), a histone methyltransferase that targets the histone H3 lysine 79 (H3K79), has been reported that its high expression is associated with various cancers, while the association between Dot1l expression and clear-cell renal cell carcinoma (ccRCC) is still unknown.We retrospectively enrolled 282 patients with ccRCC undergoing nephrectomy from a single institution between 2005 and 2007, with a median follow-up of 99 months. Dot1l expression was evaluated by immunohistochemistry in clinical specimens. We compared the clinical outcomes by Kaplan-Meier survival analyses and assessed the prognostic value of Dot1l expression. Harrell's concordance index (C-index) was used to assess the predictive accuracy of different prognostic models.Higher Dot1l expression indicated poorer OS (P<0.001) and RFS (P<0.001) in patients with ccRCC. Moreover, Dot1l expression could stratify ccRCC patients in pT stage, Fuhrman grade and SSIGN/ Leibovich subgroups, which might redefine individual risk stratification. Multivariate analyses further indicated that Dot1l expression was an independent prognostic factor for OS (P=0.007) and RFS (P=0.001). The prognostic accuracy of conventional prognostic models was notably improved with Dot1l integration. Two nomograms and calibration plots were built to predict OS and RFS for patients with ccRCC and performed better based on C-index value.Dot1l expression is a promising independent prognostic indicator for postoperative recurrence and survival of patients with ccRCC.
| S-EPMC5356697 | biostudies-other
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.
| S-EPMC6778431 | biostudies-literature
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.
| S-EPMC8791850 | biostudies-literature
Project description:What is the leading molecular mechanism that causes broad resistance to systemic therapies remains a key question in renal cancer related research. We explored associations of TRIP13 expression with the clinical course using the tissue microarray (TMA). The TMA contained specimens from 87 patients diagnosed with clear cell renal cell carcinoma (ccRCC). We performed immunohistochemistry to investigate TRIP13 protein expression levels. The overall survival (OS) was analyzed using the Kaplan-Meier method and log-rank statistics. Univariate and multivariate analyses were conducted using Cox proportional hazard models. Median follow up for the TMA cohort was 7.0 years. Tissues from 28.74% of patients demonstrated high TRIP13 expression. Mean TRIP13 expression in TRIP13-rich tumors was significantly higher comparing to adjacent normal tissues (P < 0.05). TRIP13 expression did not significantly correlate with stage nor tumor grade (P > 0.05). Elevated expression of TRIP13 served as an independent unfavorable prognostic indicator of survival in ccRCC (P < 0.05). TRIP13 overexpression predicts poor prognosis in ccRCC. Together with the emerging reports, this observation raises a suspicion that TRIP13 is a substantial driver of resistance to systemic therapies against kidney cancer.
| S-EPMC7539765 | biostudies-literature
Project description:Previous studies have demonstrated abnormal H3K27 methylation status during clear cell renal cell carcinoma (ccRCC) carcinogenesis, and have suggested that the histone H3K27 demethylases, jumonji domain-containing protein 3 (JMJD3) and ubiquitously-transcribed TPR gene on the X chromosome, are important regulatory factors that alter H3K27 methylation status. The present study aimed to explore the prognostic value of JMJD3 in patients with ccRCC. A total of 331 ccRCC samples were stained for JMJD3 by immunohistochemistry. Stage, Size, Grade and Necrosis (SSIGN) and University of California Los Angeles Integrated Staging System (UISS) scores were applied to stratify risks. Survival analyses were performed through the Kaplan-Meier estimator method and Cox proportional hazard model. The results revealed that JMJD3 expression in ccRCC was significantly increased compared with that in the peritumoral tissue (P<0.001) and negatively associated with a number of other clinicopathological characteristics. Kaplan-Meier estimator and multivariate analyses revealed that decreased tumoral JMJD3 expression was associated with OS (hazard ratio, 2.141; P=0.003), and DFS prediction (hazard ratio, 1.737; P=0.033). In addition, following stratification of patients into three risk levels using the SSIGN and UISS scores, decreased tumoral JMJD3 expression was associated with shorter OS (P=0.003 for SSIGN and UISS scores) and DFS (P=0.007 for SSIGN and P=0.041 for UISS score) in the intermediate risk groups. The results from the present study suggest that JMJD3 is a novel prognostic marker for patients with ccRCC and is of particular significance in patients with intermediate-risk disease.
| S-EPMC5529904 | biostudies-other
Project description:BackgroundGrowing findings have demonstrated that interferon regulatory transcription factor (IRF) family members are linked to the progression of various cancers. However, the roles of IRFs in clear cell renal cell carcinoma (ccRCC) remain undefined. Herein, we conducted a comprehensive analysis using the bioinformatics method to evaluate the expression patterns, clinical significance, and regulation of IRFs-related mechanisms in patients with ccRCC.MethodsData from the Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGA), and Gene Expression Omnibus (GEO) databases were used for investigation comprehensively. Specifically, we carried out a series of analyses to identify the candidate IRF and to explore its potential action mechanisms using the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. What is more, we emphatically investigate the association of candidate IRF with tumor immunity in ccRCC through the CIBERSORT algorithm, TIMER and GEPIA databases.ResultsHerein, IRF3 was identified as candidate IRF, which was highly expressed in ccRCC, and its overexpression was significantly associated with worse clinical outcomes and adverse overall survival. Uni- and multi-variate Cox regression analysis demonstrated that IRF3 overexpression was an independent predictor of worse prognosis. Functional enrichment analysis showed that IRF3 might participate in several cancer-related biological processes and signaling pathways, thereby promoting the progression of ccRCC. Additionally, we found that IRF3 was remarkably associated with tumor-infiltrating immune cells (TIICs) and various immune-related genes.ConclusionHerein, we identified IRF3 from the IRF gene family members, which could serve as promising prognostic marker and therapeutic target in ccRCC.
| S-EPMC8454526 | biostudies-literature
Project description:Mucin-4 (MUC4), a member of membrane-bound mucins, has been reported to exert a large variety of distinctive roles in tumorigenesis of different cancers. MUC4 is aberrantly expressed in clear-cell renal cell carcinoma (ccRCC) but its prognostic value is still unveiled. This study aims to assess the clinical significance of MUC4 expression in patients with ccRCC.The expression of MUC4 was assessed by immunohistochemistry in 198 patients with ccRCC who underwent nephrectomy retrospectively in 2003 and 2004. Sixty-seven patients died before the last follow-up in the cohort. Kaplan-Meier method with log-rank test was applied to compare survival curves. Univariate and multivariate Cox regression models were applied to evaluate the prognostic value of MUC4 expression in overall survival (OS). The predictive nomogram was constructed based on the independent prognostic factors. The calibration was built to evaluate the predictive accuracy of nomogram.In patients with ccRCC, MUC4 expression, which was determined to be an independent prognostic indicator for OS (hazard ratio [HR] 3.891; P?<?0.001), was negatively associated with tumor size (P?=?0.036), Fuhrman grade (P?=?0.044), and OS (P?<?0.001). The prognostic accuracy of TNM stage, UCLA Integrated Scoring System (UISS), and Mayo clinic stage, size, grade, and necrosis score (SSIGN) prognostic models was improved when MUC4 expression was added. The independent prognostic factors, pT stage, distant metastases, Fuhrman grade, sarcomatoid, and MUC4 expression were integrated to establish a predictive nomogram with high predictive accuracy.MUC4 expression is an independent prognostic factor for OS in patients with ccRCC.
| S-EPMC4998678 | biostudies-literature
Project description:Background: Clear cell renal cell carcinoma (ccRCC) constitutes the commonest kidney malignancy. Immunogenic cell death (ICD) is a type of regulated cell death (RCD), which sufficiently activates adaptive immunity. However, ICD's involvement in cancer development is unclear, as well as the associations of ICD effectors with ccRCC prognosis. Methods: RNA-sequencing expression profiles of ccRCC in The Cancer Genome Atlas (TCGA) and normal samples in Gene Expression Omnibus (GEO) were comprehensively investigated. Consensus clustering analysis was employed to determine subgroup members linked to ICD-related genes. Functional enrichment analysis was utilized for the examination of TLR4's biological role, and in vitro cellular assays were utilized for further confirmation. We also used Kaplan-Meier (KM) and Cox regression analyses to assess TLR4's prognostic value. Finally, "CIBERSORT" was employed for immune score evaluation. Results: The associations of ICD effectors with ccRCC prognosis were examined based on TCGA, and 12 genes showed upregulation in ccRCC tissue specimens. Meanwhile, ccRCC cases with upregulated ICD-related genes had increased overall survival. Among these ICD-related genes, TLR4 was selected for subsequent analysis. TLR4 was upregulated in ccRCC samples and independently predicted ccRCC. TLR4 also enhanced the proliferative, migratory and invasive abilities in cultured ccRCC cells. Moreover, TLR4 had close relationships with immune checkpoints and infiltrated immune cells. ccRCC cases with elevated TLR4 expression had prolonged overall survival, suggesting a prognostic value for TLR4. Finally, a pan-cancer analysis demonstrated TLR4 had differential expression in various malignancies in comparison with normal tissue samples. Conclusions: This study revealed prognostic values for ICD-associated genes, particularly TLR4, and experimentally validated the inducing effects of TLR4 on ccRCC progression in vitro. We also demonstrated the associations of TLR4 with immune cell infiltration, providing a novel strategy for prognostic evaluation and a novel therapeutic target in ccRCC.
| S-EPMC10414050 | biostudies-literature
Project description:BACKGROUND:Although clear cell renal cell carcinoma (ccRCC) is well known as a highly immunogenic tumor, only a small subset of patients could benefit from current immunotherapy, which might be due to the heterogeneity of immune microenvironment in ccRCC. So, it is meaningful to explore novel immunotherapy or combination therapy for improving therapeutic efficacy. HHLA2, a newly discovered B7 family member, is prevalently expressed in numerous tumors, including ccRCC. This study aimed to investigate the prognostic impact of HHLA2/PD-L1 co-expression and its relationship with tumor-infiltrating lymphocytes (TILs). METHODS:The expression levels of HHLA2, PD-L1, CD8, and CD4 in cancer tissues from cases (206 in the training cohort and 197 in the validation cohort) with surgically resectable primary ccRCC were evaluated by immunohistochemistry. RESULTS:The positive rates of HHLA2 were much higher than those of PD-L1 in ccRCC tissues. HHLA2-positive expression was significantly associated with necrosis, microvascular invasion, advanced Fuhrman nuclear, and TNM stage and indicated a shorter progression-free survival (PFS) and overall survival (OS) in both cohorts. Moreover, patients with HHLA2/PD-L1 co-expression suffered the highest risk of disease progression and death by a significant margin. Besides, HHLA2/PD-L1 co-expression was significantly associated with a high density of CD8+ and CD4+ TILs. Notably, a new immune classification, based on HHLA2/PD-L1 co-expression and TILs, successfully stratified PFS and OS, especially in patients with TILs positivity. CONCLUSIONS:The expression of HHLA2 is more frequent than PD-L1 in ccRCC. HHLA2/PD-L1 co-expression had an adverse impact on the prognoses of patients with ccRCC; this finding provides a rationale for combination immunotherapy with anti-HHLA2 and PD-L1 blockage for patients with ccRCC in the future.
| S-EPMC7057441 | biostudies-literature
Project description:Clear cell renal cell carcinoma (ccRCC) is one of the most common types of malignant tumors and early detection contributes to a better prognosis. Finding new biomarkers for the diagnosis or treatment remains meaningful. DEF6 guanine nucleotide exchange factor (DEF6) is upregulated in ccRCC compared to normal controls, but the relationship between DEF6 expression and prognosis in ccRCC is unclear. Moreover, the potential biological functions of DEF6 in ccRCC remains unclear. In the present study, the Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), TISIDB and the clinical database of the Peking University First Hospital were used to analyze DEF6 expression in ccRCC. Immunohistochemistry (IHC), western blotting and reverse transcription‑quantitative PCR were used to examine the DEF6 protein and mRNA expression levels in cell lines and clinical samples. Subsequently, the Kaplan‑Meier method and Cox regression analyses were used to determine the impact of DEF6 expression on the overall survival of patients alongside other clinical variables in both the TCGA database and the present clinical database. The results showed that both DEF6 mRNA and protein expression levels were upregulated in ccRCC compared to normal controls. The Kaplan‑Meier survival analysis showed that patients with high DEF6 expression had poor prognoses from both the TCGA database and the present clinical database. Univariate survival analysis and multivariate survival analysis revealed that DEF6 could be an independent prognostic factor for ccRCC. Additionally, bioinformatics analysis indicated that differentially expressed genes related to DEF6 expression influenced ccRCC by regulating the tumor immune microenvironment. In conclusion, overexpression of DEF6 is significantly correlated with a poor prognosis for patients with ccRCC and DEF6 may influence the biological processes involved with ccRCC by regulating the immune microenvironment.
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