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Expression data from 786-O renal cell cancer cells treated with pentamidine

ABSTRACT: While early stages of clear cell renal cell carcinoma (ccRCC) are curable, survival outcome for metastatic ccRCC remains poor. The purpose of the current study was to apply a new individualized bioinformatics analysis (IBA) strategy to these transcriptome data in conjunction with Gene Set Enrichment Analysis of the Connectivity Map (C-MAP) database to identify and reposition FDA-approved drugs for anti-cancer therapy. We demonstrated that one of the drugs predicted to revert the RCC gene signature towards normal kidney, pentamidine, is effective against RCC cells in culture and in a RCC xenograft model. Most importantly, pentamidine slows tumor growth in the 786-O human ccRCC xenograft mouse model. To determine which genes are regulated by pentamidine in a human RCC cell line, 786-O, we treated these cells with pentamidine and performed transcriptional profiling analysis. We used microarrays to determine the set of genes regulated by pentamidine in 786-O renal cell cancer cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE54709 | GEO | 2014/08/05

SECONDARY ACCESSION(S): PRJNA237461

REPOSITORIES: GEO

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Expression data from 786-O renal cell cancer cells treated with pentamidine

Project description:While early stages of clear cell renal cell carcinoma (ccRCC) are curable, survival outcome for metastatic ccRCC remains poor. The purpose of the current study was to apply a new individualized bioinformatics analysis (IBA) strategy to these transcriptome data in conjunction with Gene Set Enrichment Analysis of the Connectivity Map (C-MAP) database to identify and reposition FDA-approved drugs for anti-cancer therapy. We demonstrated that one of the drugs predicted to revert the RCC gene signature towards normal kidney, pentamidine, is effective against RCC cells in culture and in a RCC xenograft model. Most importantly, pentamidine slows tumor growth in the 786-O human ccRCC xenograft mouse model. To determine which genes are regulated by pentamidine in a human RCC cell line, 786-O, we treated these cells with pentamidine and performed transcriptional profiling analysis. We used microarrays to determine the set of genes regulated by pentamidine in 786-O renal cell cancer cells. Total RNA was isolated from 786-O cells treated with 25 Î¼M pentamidine or vehicle control (DMSO) for 6 hours and hybridized to Affymetrix microarrays.

2014-08-05 | E-GEOD-54709 | biostudies-arrayexpress

The Urinary Peptidome Identifies Prognostic Biomarkers for Small Renal Masses

Project description:Purpose: Renal cell carcinoma (RCC) is often diagnosed incidentally as an early-stage small renal mass (SRM; pT1a, ≤ 4 cm). Increasing concerns surrounding the overtreatment of patients with benign or clinically indolent tumors has led to a shift in current treatment recommendations, especially for elderly and infirm patients. There are currently no available biomarkers to accurately stratify patients according to risk. Therefore, we set out to identify early biomarkers of RCC progression. Experimental Design: We employed label-free LC-MS/MS and targeted parallel-reaction monitoring (PRM) to identify early, non-invasive diagnostic and prognostic biomarkers for early-stage RCC-SRMs. In total, we evaluated 115 urine samples, including 33 renal oncocytoma (≤ 4 cm) cases, 30 progressive and 26 non-progressive clear cell RCC-SRM (ccRCC-SRM) cases, in addition to 26 healthy controls. Results: We identified nine endogenous peptides which displayed significantly elevated expression in ccRCC-SRMs relative to healthy controls. Peptides NVINGGSHAGNKLAMQEF, VNVDEVGGEALGRL, and VVAGVANALAHKYH showed significantly elevated expression in ccRCC-SRMs relative to renal oncocytoma. Additionally, peptides SHTSDSDVPSGVTEVVVKL and IVDNNILFLGKVNRP displayed significantly elevated expression in progressive relative to non-progressive ccRCC-SRMs. Peptide SHTSDSDVPSGVTEVVVKL showed the most significant discriminatory ability (AUC: 0.76, 95% CI: 0.62 to 0.90, p = 0.0027). Patients with elevated SHTSDSDVPSGVTEVVVKL expression had significantly shorter overall survival (HR: 4.13, 95% CI: 1.09 to 15.65, p = 0.024) compared to patients with lower expression. Conclusions: Our in-depth peptidomic analysis identified novel biomarkers for early-stage RCC-SRMs. Characterization of urinary peptides may provide insight into early RCC progression and could potentially help assign patients to appropriate management programs.

2019-08-08 | PXD013111 | Pride

Effect of everolimus on clear cell renal cell carcinoma (ccRCC) cell lines - parental and stem cells

Project description:The aim of this study was to compare effect of everolimus on growth of different renal cell carcinoma (RCC) populations and develop design for experiments to measure the early response of everolimus in clear cell RCC (ccRCC) cell lines including renal cancer stem cells. Gene expression profiling using microarray was performed to determine the early response to everolimus after 3 days of treatment with optimizied concentration of drug in two ccRCC cell lines 1) parental clear cell renal cell carcinoma ccRCC-PCSC (HKPCSC -human parental kidney cancer stem cells) and 2) ccRCC-CSC - clear cell renal cell carcinoma -cancer stem cells (HKCSC - human kidney cancer stem cells).

2018-05-31 | GSE106819 | GEO

DNA Copy-Number Alterations in clear-cell Renal Cell Carcinoma (ccRCC) Tumors and Tumorgrafts for samples deficient in BAP1 or PBRM1

Project description:Renal cell carcinoma (RCC) exhibits some unusual features and genes commonly mutated in cancer are rarely mutated in clear-cell RCC (ccRCC), the most common type. The most prevalent genetic alteration in ccRCC is the inactivation of the tumor suppressor gene VHL. Using whole-genome and exome sequencing we discovered BAP1 as a novel tumor suppressor in ccRCC that shows little overlap with mutations in PBRM1, another recent tumor suppressor. Whereas VHL was mutated in 81% of the patients (142/176), PBRM1 was lost in 58% and BAP1 in 15% of the patients analyzed. All these tumor suppressor genes are located in chromosome 3p, which is partially or completely lost in most ccRCC patients. However, BAP1 but not PBRM1 loss was associated with higher Fuhrman grade and, therefore, poorer outcome. Xenograft tumors (tumorgrafts) implanted orthotopically in mice retained >92% of mutations and exhibited similar DNA copy number alterations to corresponding primary tumors. Thus, after inactivation of VHL, the acquisition of a mutation in BAP1 or PBRM1 defines a different program that might alter the fate of the patient. Our results establish the foundation for an integrated pathological and molecular genetic classification of about 70% of ccRCC patients, paving the way for subtype-specific treatments exploiting genetic vulnerabilities. The genomic DNA of clear-cell renal cell carcinoma (ccRCC) primary tumors, tumors growing in immunodeficient mice (tumorgrafts), and normal samples were labeled and hybridized to Affymetrix SNP arrays 6.0.

2012-06-09 | E-GEOD-25540 | biostudies-arrayexpress

Integrative Epigenetic and Gene Expression Analysis of Renal Tumor Progression to Metastasis

Project description:Renal cell carcinoma (RCC) is among the ten most common malignancies. By far, the most common histology is clear cell (ccRCC). The Cancer Genome Atlas and other large scale sequencing studies of ccRCC have been integral to the current understanding of molecular events underlying RCC and its biology. However, these data sets have focused on primary RCC which often demonstrates indolent behavior. In contrast, metastatic disease is the major cause of mortality associated with ccRCC. However, data sets examining metastatic tumor are sparse. We therefore undertook an integrative analysis of gene expression and DNA methylome profiling of metastatic ccRCC in addition to primary RCC and normal kidney. Integrative analysis of the methylome and transcriptome identified over 30 RCC specific genes whose mRNA expression inversely correlated with promoter methylation including several known targets of hypoxia inducible factors (HIFs). Notably, genes encoding several metabolism-related proteins were identified as differentially regulated via methylation. Collectively, our data provide novel insight into biology of aggressive RCC. Furthermore, they demonstrate a clear role for epigenetics in the promotion of HIF signaling and invasive phenotypes in renal cancer.

2018-10-16 | GSE105288 | GEO

Molecular Genetic Classification of clear-cell Renal Cell Carcinoma (ccRCC) based on the Gene Expression Profiling of Tumors and Tumorgrafts deficient for BAP1 or PBRM1

Project description:Renal cell carcinoma (RCC) exhibits some unusual features and genes commonly mutated in cancer are rarely mutated in clear-cell RCC (ccRCC), the most common type. The most prevalent genetic alteration in ccRCC is the inactivation of the tumor suppressor gene VHL. Using whole-genome and exome sequencing we discovered BAP1 as a novel tumor suppressor in ccRCC that shows little overlap with mutations in PBRM1, another recent tumor suppressor. Whereas VHL was mutated in 81% of the patients (142/176), PBRM1 was lost in 58% and BAP1 in 15% of the patients analyzed. All these tumor suppressor genes are located in chromosome 3p, which is partially or completely lost in most ccRCC patients. However, BAP1 but not PBRM1 loss was associated with higher Fuhrman grade and, therefore, poorer outcome. Xenograft tumors (tumorgrafts) implanted orthotopically in mice exhibited similar gene expression profiling to corresponding primary tumors. Gene expression profiling of tumors and tumorgrafts displayed different signatures for BAP1- and PBRM1-deficient samples. Thus, after inactivation of VHL, the acquisition of a mutation in BAP1 or PBRM1 defines a different program that might alter the fate of the patient. Our results establish the foundation for an integrated pathological and molecular genetic classification of about 70% of ccRCC patients, paving the way for subtype-specific treatments exploiting genetic vulnerabilities. The RNA of clear-cell renal cell carcinoma (ccRCC) primary tumors, tumors growing in immunodeficient mice (tumorgrafts), and normal kidney cortices were labeled and hybridized to Affymetrix Human Genome U133 Plus 2.0 arrays.

2012-06-09 | E-GEOD-36895 | biostudies-arrayexpress

Quantitative phosphoproteomics analysis uncovers CDK1- and PAK2-mediated malignant signaling pathways in clear cell Renal Cell Carcinoma

Project description:Clear cell Renal Cell Carcinoma (ccRCC) is among the 10 most common cancers and causes more than 140,000 deaths worldwide every year. In order to elucidate the underlying molecular mechanisms orchestrated by phosphorylation modifications, we performed a comprehensive quantitative phosphoproteomics characterization of ccRCC tumor and normal adjacent tissues. Here, we identified 16,253 phosphopeptides, of which more than 9,000 were quantified. Our in-depth analysis revealed 1,336 phosphopeptides to be differentially regulated between tumor and normal tissues. Moreover, our data reveals that significantly up-regulated phosphoproteins are associated with cytoskeletal re-organization which suggests migratory and invasive behavior of renal tumors. This is supported by a pronounced mesenchymal profile of ccRCC phosphorylation events. Our rigorous characterization of the renal phosphoproteome also revealed that both EGFR and VEGFR are the most important mediators of phospho signaling in RCC pathogenesis. Furthermore, we determined the kinases PAK2, CDK1, Erk1 and Erk2 to be master kinases that are responsible for phosphorylations of many substrates associated with cell proliferation, inflammation and migration. These master kinases are targetable by inhibitory FDA-approved drugs such as fostamatinib and minocycline, which can serve as novel therapeutic agents for ccRCC treatment.

2023-03-10 | PXD028428 | Pride

microRNA Profiling in Metastatic Renal Cell Carcinoma

Project description:We performed a microRNA (miRNA) microarray on 10 metastatic RCC tumors and compared differential miRNA expresison to 19 primary clear cell renal cell carcinomas (ccRCC). We found there were 65 significantly dysregulated miRNAs; 9 miRNAs were significantly upregulated and 56 miRNAs were significantly downregulated in metastatic RCC when compared to primary clear cell renal cell carcinoma. miRNA microarray was performed on 10 metastatic RCC tumors

2012-08-13 | E-GEOD-39440 | biostudies-arrayexpress

Genome wide expression change by 786-O cells treated with MST1/2 inhibitor XMU-MP-1

Project description:We aim to the investigate the role of MST1/2 inhibitor XMU-MP-1 in kindy renal clear cell carcinoma (ccRCC) progression. 786-O cells were used as the model.

2022-02-28 | GSE197468 | GEO

Systematic Analysis of Transcriptomic Profile of Renal Cell Carcinoma under Long-Term Hypoxia using Next-Generation Sequencing and Bioinformatics

Project description:Patients with clear cell renal cell carcinoma (ccRCC) are often diagnosed with both von Hippel-Lindau (VHL) mutations and the constitutive activation of hypoxia-inducible factor-dependent signaling. In this study, we investigated the effects of long-term hypoxia in 786-O, a VHL-defective renal cell carcinoma cell line, to identify potential genes and microRNAs associated with tumor malignancy. The transcriptomic profiles of 786-O under normoxia, short-term hypoxia, and long-term hypoxia were analyzed using next-generation sequencing. The results showed that long-term hypoxia promoted the ability of colony formation and transwell migration compared to normoxia. In addition, the differentially expressed genes induced by long-term hypoxia were involved in various biological processes including cell proliferation, the tumor necrosis factor signaling pathway, basal cell carcinoma, and cancer pathways. The upregulated (L1CAM and FBN1) and downregulated (AUTS2, MAPT, AGT, and USH1C) genes in 786-O under long-term hypoxia were also observed in clinical ccRCC samples along with malignant grade. The expressions of these genes were significantly correlated with survival outcomes in patients with renal cancer. We also found that long-term hypoxia in 786-O resulted in decreased expressions of hsa-miR-100 and has-miR-378, and this effect was also observed in samples of metastatic ccRCC compared to samples of non-metastatic ccRCC. These findings may provide a new direction for the study of potential molecular mechanisms associated with the progression of ccRCC.

2017-12-12 | GSE107848 | GEO

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