PAI-1 expression and its regulation by promoter 4G/5G polymorphism in clear cell renal cell carcinoma

2011 ◽  
Vol 64 (10) ◽  
pp. 893-897 ◽  
Author(s):  
Jung-Woo Choi ◽  
Ju-Han Lee ◽  
Hong Seok Park ◽  
Young-Sik Kim
Keyword(s):  
Renal Cell Carcinoma ◽  
Distant Metastasis ◽  
Clear Cell ◽  
Disease Free Survival ◽  
Nuclear Grade ◽  
Cell Renal Cell Carcinoma ◽  
Free Survival ◽  
High Nuclear Grade ◽  
Disease Free ◽  
Pai 1

AimsTo characterise patients with high plasminogen activator inhibitor-1 (PAI-1) expression as oral PAI-1 antagonists are currently in preclinical trials, and to determine whether the PAI-1 promoter 4G/5G polymorphism regulates PAI-1 expression in clear cell renal cell carcinoma (CCRCC).MethodsPAI-1 expression was examined by immunohistochemistry in 69 CCRCC specimens. In addition, the promoter 4G/5G polymorphism was investigated by both allele-specific PCR and direct DNA sequencing.ResultsPAI-1 was overexpressed in 25/69 (36.2%) patients with CCRCC. PAI-1 staining was intense in tumour cells with a high Fuhrman nuclear grade and in spindle-shaped tumour cells. PAI‐1 expression was significantly associated with older age at diagnosis (p=0.027), high nuclear grade (p<0.001), advanced clinical stage (p=0.030) and distant metastasis (p=0.009). In survival analyses, PAI-1 expression was correlated with disease-free survival in Kaplan–Meier curves (p=0.015) but was not significant in the Cox hazards model (p=0.527). The frequencies of the promoter polymorphism were 24.6% (17/69) 4G/4G, 43.5% (30/69) 4G/5G and 31.9% (22/69) 5G/5G. The homozygous 4G/4G or 5G/5G group showed a tendency for a high nuclear grade (p=0.05) but the 4G/5G polymorphism was not related to other prognostic parameters. PAI-1 expression was poorly correlated with its promoter 4G/5G polymorphism (Spearman ρ=0.088).ConclusionsCCRCC with high PAI-1 expression is characterised by older age, high nuclear grade, advanced stage, distant metastasis and/or shortened disease-free survival. PAI-1 expression is not affected by the promoter 4G/5G polymorphism.

scholarly journals Integrative Bioinformatics Analysis Reveals New Prognostic Biomarkers of Clear Cell Renal Cell Carcinoma

2014 ◽  
Vol 60 (10) ◽  
pp. 1314-1326 ◽  
Author(s):  
Henriett Butz ◽  
Peter M Szabó ◽  
Roy Nofech-Mozes ◽  
Fabio Rotondo ◽  
Kalman Kovacs ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Disease Free Survival ◽  
Migration And Invasion ◽  
Data Sets ◽  
Cell Renal Cell Carcinoma ◽  
Free Survival ◽  
Pathogenic Factors ◽  
Disease Free

Abstract BACKGROUND The outcome of clear cell renal cell carcinoma (ccRCC) is still unpredictable. Even with new targeted therapies, the average progression-free survival is dismal. Markers for early detection and progression could improve disease outcome. METHODS To identify efficient and hitherto unrecognized pathogenic factors of the disease, we performed a uniquely comprehensive pathway analysis and built a gene interaction network based on large publicly available data sets assembled from 28 publications, comprising a 3-prong approach with high-throughput mRNA, microRNA, and protein expression profiles of 593 ccRCC and 389 normal kidney samples. We validated our results on 2 different data sets of 882 ccRCC and 152 normal tissues. Functional analyses were done by proliferation, migration, and invasion assays following siRNA (small interfering RNA) knockdown. RESULTS After integration of multilevel data, we identified aryl-hydrocarbon receptor (AHR), grainyhead-like-2 (GRHL2), and KIAA0101 as new pathogenic factors. GRHL2 expression was associated with higher chances for disease relapse and retained prognostic utility after controlling for grade and stage [hazard ratio (HR), 3.47, P = 0.012]. Patients with KIAA0101-positive expression suffered worse disease-free survival (HR, 3.64, P &lt; 0.001), and in multivariate analysis KIAA0101 retained its independent prognostic significance. Survival analysis showed that GRHL2- and KIAA0101-positive patients had significantly lower disease-free survival (P = 0.002 and P &lt; 0.001). We also found that KIAA0101 silencing decreased kidney cancer cell migration and invasion in vitro. CONCLUSIONS Using an integrative system biology approach, we identified 3 novel factors as potential biomarkers (AHR, GRHL2 and KIAA0101) involved in ccRCC pathogenesis and not linked to kidney cancer before.

scholarly journals Clear Cell Renal Cell Carcinoma with Biallelic Inactivation of CDKN2A/B on 9p21 have Distinct Gene Expression Signature and are Associated with Poor Prognosis

2017 ◽  
Author(s):  
Andrew H. Girgis
Keyword(s):  
Gene Expression ◽  
Renal Cell Carcinoma ◽  
Clear Cell ◽  
Disease Free Survival ◽  
Homozygous Deletion ◽  
Heterozygous Deletion ◽  
Cell Renal Cell Carcinoma ◽  
Cancer Specific Survival ◽  
Free Survival ◽  
Disease Free

AbstractPurposeThe clinical implications of biallelic inactivation of CDKN2A/B in clear cell renal cell carcinoma (ccRCC) and relevant dysregulated biological pathways and gene signatures were investigated.Materials and MethodsData were obtained from the TCGA data set and validated using Project GENIE and previously published dataset. CDKN2A/B allelic status was classified into 3 groups, including biallelic CDKN2A/B inactivation (homozygous deletion or combined heterozygous deletion and mutation), monoallelic CDKN2A/B loss (heterozygous deletion or mutation) and absent CDKN2A/B allelic loss. Univariate and multivariate cancer-specific survival and disease-free survival analyses were performed. Integrated analyses of copy number, gene expression (mRNA and miRNA), protein expression and methylation changes were conducted.ResultsOf 440 patients with ccRCC 17 (3.9%) had biallelic CDKN2A/B inactivation and 116 (26.4%) had monoallelic CDKN2A/B loss. CDKN2A/B allelic inactivation was associated with late tumor stage, high histological grade, presence of metastasis and greater tumor size. Patients with biallelic deletion of CDKN2A/B showed significantly worse cancer-specific survival and disease-free survival (p<0.0001). Significant co-occurrence of MTAP homozygous deletion was observed in CDKN2A/B biallic inactivated tumors (46.7%; p<0.001). Significant underexpression of CDKN2A/B was observed in biallelic inactivated tumors at the mRNA and protein levels. miR-21 was the most highly expressed miRNA in biallelic inactivated tumors. Biallelic inactivated tumors were significantly enriched for genes related to activation of ATR in response to replication stress and miR-21 target genes.ConclusionsCDKN2A/B biallelic inactivation may be a prognostic marker for ccRCC and is associated with distinct dysregulation of gene expression signatures.

scholarly journals Molecular Signatures of Localized Clear Cell Renal Cell Carcinoma to Predict Disease-Free Survival after Nephrectomy

2009 ◽  
Vol 18 (3) ◽  
pp. 894-900 ◽  
Author(s):  
Tobias Klatte ◽  
David B. Seligson ◽  
Jeffrey LaRochelle ◽  
Brian Shuch ◽  
Jonathan W. Said ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Disease Free Survival ◽  
Molecular Signatures ◽  
Cell Renal Cell Carcinoma ◽  
Free Survival ◽  
Disease Free

Utility of the Apparent Diffusion Coefficient for Distinguishing Clear Cell Renal Cell Carcinoma of Low and High Nuclear Grade

2010 ◽  
Vol 195 (5) ◽  
pp. W344-W351 ◽  
Author(s):  
Andrew B. Rosenkrantz ◽  
Benjamin E. Niver ◽  
Erin F. Fitzgerald ◽  
James S. Babb ◽  
Hersh Chandarana ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Diffusion Coefficient ◽  
Apparent Diffusion Coefficient ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Nuclear Grade ◽  
Cell Renal Cell Carcinoma ◽  
High Nuclear Grade ◽  
Apparent Diffusion

Vasohibin-1 is a new predictor of disease-free survival in operated patients with renal cell carcinoma

2013 ◽  
Vol 66 (7) ◽  
pp. 613-619 ◽  
Author(s):  
Naoki Kanomata ◽  
Yasufumi Sato ◽  
Yoshiyuki Miyaji ◽  
Atsushi Nagai ◽  
Takuya Moriya
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Clear Cell Carcinoma ◽  
Disease Free Survival ◽  
Vegf Receptor ◽  
Clinicopathological Factors ◽  
Free Survival ◽  
Disease Free

BackgroundVasohibin-1 (VASH1) is an endothelium-produced angiogenesis inhibitor. Renal cell carcinoma is highly vascularised, but the significance of endogenous VASH1 in renal cell carcinoma has not been defined.AimsTo identify VASH1 expression and its possible relationship with various clinicopathological factors and prognosis in renal cell carcinoma.MethodsA retrospective analysis of 122 tumours obtained from 118 consecutive patients with renal cell carcinoma was performed. The expression patterns of VASH1, CD31, vascular endothelial growth factor (VEGF) and VEGF receptor type 2 (VEGFR2) were examined immunohistochemically and their relationships with clinicopathological factors were analysed.ResultsMicrovessel density, VASH1 and VEGFR2 expression were significantly higher in clear cell carcinoma than in other subtypes. The VEGF expression pattern differed significantly between clear cell carcinoma and other histological subtypes. VASH1, pT factor and TNM stage were significantly associated with disease-free survival (p=0.030, p = 0.0012 and p = 0.0018, respectively). Cox models of multivariable disease-free survival analyses indicated that VASH1 and stage are independent prognostic factors (p=0.019 and p = 0.024).ConclusionsVASH1 expression may be useful for estimating the prognosis of renal cell carcinoma. Further studies of the role of VASH1 in renal cell carcinoma involving larger sample sizes are warranted.

scholarly journals Bioinformatics analysis of C3 and CXCR4 demonstrates their potential as prognostic biomarkers in clear cell renal cell carcinoma (ccRCC)

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jing Quan ◽  
Yuchen Bai ◽  
Yunbei Yang ◽  
Er Lei Han ◽  
Hong Bai ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Therapeutic Targets ◽  
Disease Free Survival ◽  
Prognostic Biomarkers ◽  
Hub Genes ◽  
Cell Renal Cell Carcinoma ◽  
Upregulated Genes

Abstract Background The molecular prognostic biomarkers of clear cell renal cell carcinoma (ccRCC) are still unknown. We aimed at researching the candidate biomarkers and potential therapeutic targets of ccRCC. Methods Three ccRCC expression microarray datasets (include GSE14762, GSE66270 and GSE53757) were downloaded from the gene expression omnibus (GEO) database. The differentially expressed genes (DEGs) between ccRCC and normal tissues were explored. The potential functions of identified DEGs were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). And then the protein - protein interaction network (PPI) was established to screen the hub genes. After that, the expressions of hub genes were identified by the oncomine database. The hub genes’ prognostic values of patients with ccRCC were analyzed by GEPIA database. Results A total of 137 DEGs were identified by utilizing the limma package and RRA method, including 63 upregulated genes and 74 downregulated genes. It is found that 137 DEGs were mainly enriched in 82 functional terms and 24 pathways in accordance with the research results. Thirteen highest-scoring genes were screened as hub genes (include 10 upregulated genes and 3 downregulated candidate genes) by utilizing the PPI network and module analysis. Through integrating the oncoming database and GEPIA database, the author found that C3 and CXCR4 are not only overexpressed in ccRCC, but also associated with the prognosis of ccRCC. Further results could reveal that patients with high C3 expression had a poor overall survival (OS), while patients with high CTSS and TLR3 expressions had a good OS; patients with high C3 and CXCR4 expressions had a poor disease-free survival (DFS), while ccRCC patients with high TLR3 expression had a good DFS. Conclusion These findings suggested that C3 and CXCR4 were the candidate biomarkers and potential therapeutic targets of ccRCC patients.

scholarly journals Preoperative Predicting the WHO/ISUP Nuclear Grade of Clear Cell Renal Cell Carcinoma by Computed Tomography-Based Radiomics Features

2020 ◽  
Vol 11 (1) ◽  
pp. 8
Author(s):  
Claudia-Gabriela Moldovanu ◽  
Bianca Boca ◽  
Andrei Lebovici ◽  
Attila Tamas-Szora ◽  
Diana Sorina Feier ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Renal Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Predictive Ability ◽  
Nuclear Grade ◽  
Training Set ◽  
Cell Renal Cell Carcinoma ◽  
Validation Set ◽  
Sensitivity Specificity

Nuclear grade is important for treatment selection and prognosis in patients with clear cell renal cell carcinoma (ccRCC). This study aimed to determine the ability of preoperative four-phase multiphasic multidetector computed tomography (MDCT)-based radiomics features to predict the WHO/ISUP nuclear grade. In all 102 patients with histologically confirmed ccRCC, the training set (n = 62) and validation set (n = 40) were randomly assigned. In both datasets, patients were categorized according to the WHO/ISUP grading system into low-grade ccRCC (grades 1 and 2) and high-grade ccRCC (grades 3 and 4). The feature selection process consisted of three steps, including least absolute shrinkage and selection operator (LASSO) regression analysis, and the radiomics scores were developed using 48 radiomics features (10 in the unenhanced phase, 17 in the corticomedullary (CM) phase, 14 in the nephrographic (NP) phase, and 7 in the excretory phase). The radiomics score (Rad-Score) derived from the CM phase achieved the best predictive ability, with a sensitivity, specificity, and an area under the curve (AUC) of 90.91%, 95.00%, and 0.97 in the training set. In the validation set, the Rad-Score derived from the NP phase achieved the best predictive ability, with a sensitivity, specificity, and an AUC of 72.73%, 85.30%, and 0.84. We constructed a complex model, adding the radiomics score for each of the phases to the clinicoradiological characteristics, and found significantly better performance in the discrimination of the nuclear grades of ccRCCs in all MDCT phases. The highest AUC of 0.99 (95% CI, 0.92–1.00, p < 0.0001) was demonstrated for the CM phase. Our results showed that the MDCT radiomics features may play a role as potential imaging biomarkers to preoperatively predict the WHO/ISUP grade of ccRCCs.

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