Impact of frequent Bcl-2 expression on better prognosis in renal cell carcinoma patients.
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ABSTRACT:
SUBMITTER: Itoi T
PROVIDER: S-EPMC2395310 | biostudies-other | 2004 Jan
REPOSITORIES: biostudies-other
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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: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.
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Project description:IntroductionClear cell renal cell carcinoma (ccRCC) is the most common type of RCC and is associated with poor survival. However, the mechanisms underlying its development have not been thoroughly investigated. Semaphorin 6D (SEMA6D) is differentially expressed in various cancers, including lung adenocarcinoma and colorectal cancer. However, the role and mechanism of SEMA6D in ccRCC remain unexplored.Materials and methodsWe obtained 25 pairs of ccRCC tissue samples and 57 urine samples from patients with ccRCC and 52 urine samples from healthy volunteers. We performed RNA sequencing and compared the results with data from The Cancer Genome Atlas database to identify our gene of interest, SEMA6D. To verify the differential expression of SEMA6D, we used real-time quantitative polymerase chain reaction, immunohistochemistry, and enzyme-linked immunosorbent assay. Finally, we conducted in vitro proliferation, migration and invasion experiments.ResultsSEMA6D expression was significantly lower in ccRCC tissue compared to that in normal tissue. Comparative analysis of our results with data from online databases revealed that the expression level of SEMA6D in ccRCC tissue correlated with the clinical stage and pathological grade of ccRCC. Furthermore, higher SEMA6D expression was associated with improved quality of life of patients with ccRCC. In addition, the diagnostic value of SEMA6D was confirmed using data from two Gene Expression Omnibus ccRCC databases. The results showed that SEMA6D can be used as a predictor for ccRCC diagnosis, with an area under the curve of 0.9642.ConclusionSEMA6D may serve as a diagnostic and prognostic biomarker for ccRCC.
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Project description:A helpful evaluation system is crucial for the postoperative prognosis prediction of clear cell renal cell carcinoma (ccRCC) patients. This study determined the prognostic value of combining intratumoral RASSF10 expression and tumor-associated macrophages (TAMs) with the established clinicopathological indicators in ccRCC patients. RASSF10 expression was analyzed in ccRCC patient data from online databases and ccRCC cell lines. Two independent ccRCC patient cohorts were employed to examine the prognostic value of RASSF10 and other markers by immunohistochemistry (IHC) and statistical analyses. We found that RASSF10 expression was downregulated in ccRCC specimens from the TCGA datasets and three independent institutions. RASSF10 expression was negatively correlated with disease progression and TAM infiltration in ccRCC. In addition, low RASSF10 expression and high TAM infiltration predicted a high TNM stage, SSIGN score, WHO/ISUP grading, and a poor prognosis in two independent ccRCC patient cohorts. Moreover, RASSF10, CD68 or CD163, TNM stage, and SSIGN score were identified as independent risk factors in predicting ccRCC patients' prognosis. Time-dependent c-index analyses revealed that the combination of RASSF10 and TAMs resulted in a higher index than that resulting from each alone in the postoperative prognosis of ccRCC patients, and the integration of RASSF10 and TAMs with the TNM stage or SSIGN score achieved the best accuracy in assessing the prognosis of ccRCC patients. These findings were validated in the randomized training, validation, and combined cohorts. Taken together, the combination of the RASSF10-TAM classifier and current clinical parameters yields superior accuracy in predicting the ccRCC patients' postoperative outcome.
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Project description:BackgroundCDC6 (Cell division control protein 6), located at chromosome 17q21.3, plays an important role in the early stage of DNA replication and has unique functions in various malignant tumors. Here, we evaluate the relationship between CDC6 expression and oncology outcomes in patients with clear cell renal cell carcinoma (ccRCC).MethodsA retrospective analysis of 118 ccRCC patients in Affiliated Hospital of Nantong University from 2015 to 2017 was performed. Triplicate tissue microarrays (TMA) were prepared from formalin-fixed and paraffin-embedded specimens. Immunohistochemistry (IHC) was conducted to evaluate the relationship between CDC6 expression and standard pathological features and prognosis. The RNA sequencing data and corresponding clinical information were acquired from the TCGA database. GSEA was used to identify signal pathways related to CDC6. Cox regression analysis was used to assess independent prognostic factors. In addition, the relationship between CDC6 and immunity was also investigated.ResultsThe results of Kaplan-Meier curve indicated that the OS of the patients with high expression of CDC6 was shorter than that of the patients with low CDC6 expression. Integrating the TCGA database and IHC staining, the results showed that CDC6 in ccRCC tissue was obviously up-regulated compared with adjacent normal kidney tissue. The results of Logistic regression analysis demonstrated that ccRCC patients with high expression of CDC6 are more likely to develop advanced disease than ccRCC patients with low CDC6 expression. The results of GSEA showed that the high expression of CDC6 was related to multiple signaling pathways. As for immunity, it was also related to TMB, immune checkpoint molecules, tumor microenvironment and immune infiltration. There were significantly correlations with CDC6 and immune cell infiltration levels and tumor microenvironment. The results of further results of the TCGA database showed that CDC6 was obviously related to immune checkpoint molecules and immune cells.ConclusionsIncreased expression of CDC6 is a potentially prognostic factor of poor prognosis in ccRCC patients.
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Project description:Heparan sulfate-specific endosulfatase-2 (SULF-2) can modulate the signaling of heparan sulfate proteoglycan-binding proteins. The involvement of SULF-2 in cancer growth varies by cancer type. The roles of SULF-2 expression in the progression and prognosis of renal cell carcinomas (RCC) have not yet been fully clarified. In the present study, the expression levels of SULF-2 mRNA and protein in 49 clinical RCC samples were determined by RT-PCR and immunostaining. The existence of RCC with higher SULF-2 expression and lower SULF-2 expression compared to the adjacent normal kidney tissues was suggested. High SULF-2 expression was correlated with an early clinical stage and less invasive pathological factors. Low SULF-2 expression was correlated with an advanced stage and higher invasive factors. Three-year cancer-specific survival (CSS) for high SULF-2 RCC and low SULF-2 RCC were 100% and 71.4%, respectively (log-rank P = 0.0019), with a significantly shorter CSS observed in low SULF-2 RCC patients. The influence of SULF-2 expression level on Wnt/VEGF/FGF signaling, cell viability and invasive properties was examined in three RCC cell lines, Caki-2, ACHN and 786-O, using a SULF-2 suppression model involving siRNA or a SULF-2 overexpression model involving a plasmid vector. High SULF-2 expression enhanced Wnt signaling and Wnt-induced cell viability, but not cell invasion. In contrast, low levels of SULF-2 expression significantly enhanced both cell invasion and viability through the activation of VEGF/FGF pathways. RCC with lower SULF-2 expression might have a higher potential for cell invasion and proliferation, leading to a poorer prognosis via the activation of VEGF and/or FGF signaling.
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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.
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Project description:One-third of clear cell renal cell carcinoma (ccRCC) patients present with metastasis at the time of diagnosis. The prognosis of these patients is poor. To identify potential prognostic biomarkers and therapeutic targets for ccRCC, we re-evaluated published long non-coding RNA (lncRNA) expression profiling data from the Gene Expression Omnibus and ArrayExpress database. We found that five lncRNAs were differentially expressed in ccRCC and adjacent tissues. These lncRNAs were assessed in an independent cohort of 71 paired patient samples using real-time PCR. Differences in expression of three of the lncRNAs (ENSG00000177133, TCL6, and ENSG00000244020) were validated in this analysis. Kaplan-Meier analysis indicated that low expression of ENSG00000177133 and TCL6 was associated with a poor prognosis. Univariate and multivariate regression analyses demonstrated that TCL6 but not ENSG00000177133 expression was an independent predictor of ccRCC aggressiveness and had hazard ratios predictive of clinical outcome. TCL6 expression was negatively correlated with pTNM stage. Overexpression of TCL6 in 786-O and Caki-1 ccRCC cells decreased proliferation and increased apoptosis compared to controls. Our results indicate that lncRNA expression is altered in ccRCC and that decreased TCL6 expression may be an independent adverse prognostic factor in ccRCC patients.
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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.
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Project description:We enrolled a total of 277 patients who received nephrectomy due to clear cell renal cell carcinoma (ccRCC) in Zhongshan Hospital from Jan 2005 to Jun 2007. Immunohistochemistry was performed to evaluate the impact of CLEC-2 positive cell infiltration on the overall survival (OS) and recurrence-free survival (RFS) of patients with ccRCC. Kaplan-Meier analysis showed that high CLEC-2 positive cell infiltration in tumor tissue indicated poorer OS and RFS (OS, p < 0.001; RFS, p = 0.002). High CLEC-2 positive cell infiltration is also an independent risk factor for OS and RFS in multivariate analyses (OS, p = 0.004; RFS, p = 0.009). CLEC-2 positive cell infiltration could also stratify ccRCC patients' survival with University of California Integrated Staging System (UISS) stratum in the mediate-risk and high-risk groups. We constructed two nomograms incorporating parameters derived from multivariate analyses to predict patients' OS and RFS (OS, c-index 0.813; RFS, c-index 0.716). In conclusion, high CLEC-2 positive cell infiltration in ccRCC is an independent adverse prognostic factor for patients, and established nomograms based on this information could help predict ccRCC patients' OS and RFS.
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