Expression of microRNAs in rat kidney treated with a carcinogenic dose of Aristolochic Acid
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE54338 | GEO | 2015/01/15
SECONDARY ACCESSION(S): PRJNA236237
REPOSITORIES: GEO
Similar Datasets
Project description:Aristolochic Acid (AA), a natural component of Aristolochia plants found in a variety of herbal remedies and health supplements, is classified as a group 1 carcinogen by the International Agency for Research on Cancer. In order to search for miRNA regulation in AA-induced carcinogenesis, we treated rats with 10 mg/kg AA and vehicle control for 12 weeks and eight kidney samples (4 for the treatment and 4 for the control) were used for examining miRNA by deep sequencing. Profiliing of miRNA in 4 AA-treated rats and 4 control
2015-01-15 | E-GEOD-54338 | biostudies-arrayexpress
Project description:This study presents a comprehensive multi-omic analysis of upper urinary tract urothelial tumours (UTUC) and urines of patients with past exposure to carcinogenic aristolochic acid (AA). We determined complex miRNA:mRNA tumor networks and their key protein components. Tumor exome and transcriptome sequencing revealed a burden of AA-specific mutations in UTUC and identified deleteriously mutated genes and their mRNA transcripts. A subset of identified urinary miRNAs presents potential biomarkers of UTUC development or presence. Recurrent upper urinary tract carcinomas (UTUC) arise in the context of nephropathy linked to exposure to the herbal carcinogen aristolochic acid (AA). We aimed to delineate the detailed biological programs underlying UTUC tumorigenesis in patients from endemic aristolochic acid nephropathy (AAN) regions in Southern Europe, by using an integrative multi-omics analysis of UTUCs, corresponding unaffected tissues and of patient urines. Quantitative miRNA and mRNA expression profiling, immunohistochemical analysis by tissue microarrays, and exome and transcriptome sequencing were performed in UTUC and non-tumor tissues. Urinary miRNAsof cases undergoing surgery were profiled before and after UTUC resection. RNA and protein levels were analyzed using appropriate statistical tests and trend assessment. Dedicated bioinformatic tools were used for analysis of pathways, mutational signatures and result visualization. The results delineate UTUC-specific miRNA:mRNA networks comprising 89 miRNAs associated with 1862 target mRNAs and involving deregulation of cell cycle, DNA damage response, DNA repair, bladder cancer, oncogenes, tumor suppressors, chromatin structure regulators and developmental signaling pathways. Key UTUC-specific transcriptome components were confirmed at the protein level. Exome and transcriptome sequencing of UTUC revealed AA-specific COSMIC mutational signature 22, with 68-76% AA-specific, deleterious mutations propagated at the mRNA level. We next identified a signature of UTUC-specific miRNAs consistently more abundant in the patients’ urine prior to tumor resection. The gene regulation programs of AAN-associated UTUC tumors are highly complex and involve regulatory miRNAs prospectively applicable to non-invasive urine-based screening of AAN patients for cancer recurrence.
2021-06-30 | GSE166909 | GEO
Project description:This study presents a comprehensive multi-omic analysis of upper urinary tract urothelial tumours (UTUC) and urines of patients with past exposure to carcinogenic aristolochic acid (AA). We determined complex miRNA:mRNA tumor networks and their key protein components. Tumor exome and transcriptome sequencing revealed a burden of AA-specific mutations in UTUC and identified deleteriously mutated genes and their mRNA transcripts. A subset of identified urinary miRNAs presents potential biomarkers of UTUC development or presence. Recurrent upper urinary tract carcinomas (UTUC) arise in the context of nephropathy linked to exposure to the herbal carcinogen aristolochic acid (AA). We aimed to delineate the detailed biological programs underlying UTUC tumorigenesis in patients from endemic aristolochic acid nephropathy (AAN) regions in Southern Europe, by using an integrative multi-omics analysis of UTUCs, corresponding unaffected tissues and of patient urines. Quantitative miRNA and mRNA expression profiling, immunohistochemical analysis by tissue microarrays, and exome and transcriptome sequencing were performed in UTUC and non-tumor tissues. Urinary miRNAsof cases undergoing surgery were profiled before and after UTUC resection. RNA and protein levels were analyzed using appropriate statistical tests and trend assessment. Dedicated bioinformatic tools were used for analysis of pathways, mutational signatures and result visualization. The results delineate UTUC-specific miRNA:mRNA networks comprising 89 miRNAs associated with 1862 target mRNAs and involving deregulation of cell cycle, DNA damage response, DNA repair, bladder cancer, oncogenes, tumor suppressors, chromatin structure regulators and developmental signaling pathways. Key UTUC-specific transcriptome components were confirmed at the protein level. Exome and transcriptome sequencing of UTUC revealed AA-specific COSMIC mutational signature 22, with 68-76% AA-specific, deleterious mutations propagated at the mRNA level. We next identified a signature of UTUC-specific miRNAs consistently more abundant in the patients’ urine prior to tumor resection. The gene regulation programs of AAN-associated UTUC tumors are highly complex and involve regulatory miRNAs prospectively applicable to non-invasive urine-based screening of AAN patients for cancer recurrence.
2021-06-30 | GSE166907 | GEO
Project description:This study presents a comprehensive multi-omic analysis of upper urinary tract urothelial tumours (UTUC) and urines of patients with past exposure to carcinogenic aristolochic acid (AA). We determined complex miRNA:mRNA tumor networks and their key protein components. Tumor exome and transcriptome sequencing revealed a burden of AA-specific mutations in UTUC and identified deleteriously mutated genes and their mRNA transcripts. A subset of identified urinary miRNAs presents potential biomarkers of UTUC development or presence. Recurrent upper urinary tract carcinomas (UTUC) arise in the context of nephropathy linked to exposure to the herbal carcinogen aristolochic acid (AA). We aimed to delineate the detailed biological programs underlying UTUC tumorigenesis in patients from endemic aristolochic acid nephropathy (AAN) regions in Southern Europe, by using an integrative multi-omics analysis of UTUCs, corresponding unaffected tissues and of patient urines. Quantitative miRNA and mRNA expression profiling, immunohistochemical analysis by tissue microarrays, and exome and transcriptome sequencing were performed in UTUC and non-tumor tissues. Urinary miRNAsof cases undergoing surgery were profiled before and after UTUC resection. RNA and protein levels were analyzed using appropriate statistical tests and trend assessment. Dedicated bioinformatic tools were used for analysis of pathways, mutational signatures and result visualization. The results delineate UTUC-specific miRNA:mRNA networks comprising 89 miRNAs associated with 1862 target mRNAs and involving deregulation of cell cycle, DNA damage response, DNA repair, bladder cancer, oncogenes, tumor suppressors, chromatin structure regulators and developmental signaling pathways. Key UTUC-specific transcriptome components were confirmed at the protein level. Exome and transcriptome sequencing of UTUC revealed AA-specific COSMIC mutational signature 22, with 68-76% AA-specific, deleterious mutations propagated at the mRNA level. We next identified a signature of UTUC-specific miRNAs consistently more abundant in the patients’ urine prior to tumor resection. The gene regulation programs of AAN-associated UTUC tumors are highly complex and involve regulatory miRNAs prospectively applicable to non-invasive urine-based screening of AAN patients for cancer recurrence.
2021-06-30 | GSE166716 | GEO
Project description:Aristolochic acid (AA) is a nephrotoxic carcinogen responsible for acute kidney injury, chronic renal failure, and associated urothelial cancers. This study aims to determine the genes in xenobiotic metabolism pathway regulated by AA and clarify the molecular mechanism underlying their action.
2018-05-09 | GSE101530 | GEO
Project description:Aristolochic acid (AA) is an active component of herbal drugs derived from the Aristolochia species that have been used for medicinal purposes since antiquity. However, AA is genotoxic and induces tumors in animals and humans. AA induces mutations and tumors in the kidney but solely mutations in the liver. To evaluate whether miRNAs could indicate AA’s tissue-specific carcinogenicity and mutagenicity, we first conducted microarray analysis of miRNA expression in kidneys and livers of rats treated with a carcinogenic dose of AA. Then, miR-21, a biomarker for carcinogenicity, and miR-34a, a biomarker for mutagenicity, the two miRNAs whose expressions were most altered, were evaluated for their expression in the kidney (the AA’s mutagenic and carcinogenic target tissue), liver (the AA’s mutagenic target tissue), and testis, the non-target tissue where neither tumors nor mutation induction was found in previous studies and in this study. Genomic analysis of miRNA expression for kidney and liver samples showed that miRNA expression was globally changed by the treatment. Nineteen miRNAs were significantly dysregulated by the treatment in the kidney. Most of these miRNAs are related to carcinogenesis. Only one miRNA, miR-34a, was differentially expressed in the liver. Expression of miR-21 was induced in the kidney by AA treatment in a dose-dependent manner while no changes occurred in the liver or testis, indicating that the kidney is the carcinogenic target. miR-34a was dose-dependently up-regulated in the kidneys and livers of rats treated with AA, but not in the testis, suggesting that the kidney and liver are mutagenic target tissues, but the testis is not. Our results demonstrate that miRNA profiles can reflect the AA’s carcinogenicity in a tissue-specific manner while specific miRNAs can signify the target tissues for carcinogenicity or mutagenicity of AA.
2013-11-10 | GSE50946 | GEO
Project description:MicroRNAs (miRNAs) play an important role in carcinogenesis by regulating the protein translation from their targeted messenger RNAs (mRNA). Aristolochic Acid (AA) is a potent carcinogen that can induce kidney tumors in both human and experimental animals. Although the expression and roles of miRNAs have been extensively studied in cancer tissues or tissues treated by carcinogens, it is still unclear how the three levels of gene expression, including miRNA, mRNA and protein, are regulated and coordinated during the early stage of carcinogenesis. Here, we treated rats with 10 mg/kg AA or vehicle control for 12 weeks and the kidney tissues were quickly isolated and frozen immediately after the treatment. Eight kidney samples (4 for the treatment and 4 for the control) were used for analyzing miRNA and mRNA expressions with deep sequencing, and protein expressions with proteomics. MiRNA expressions were significantly changed by AA treatment. The treated samples were well separated from the control samples in both principal component analysis (PCA) and hierarchical clustering analysis (HCA). Quantitative measurements of six miRNAs using TaqMan real-time PCR were consistent with the deep sequencing results in terms of both direction and magnitude of gene expression change. Sixty-three miRNAs (adjusted p value < 0.05 and fold change > 1.5), 6,794 mRNAs (adjusted p value < 0.05 and fold change > 2.0), and 800 proteins (fold change > 2.0) were significantly altered by AA treatment. By combining the results of a computational target predicting algorithm, and the mRNA and protein expression data, 143 genes were found by the differentially expressed miRNAs (DEMs). The DEM-targeted genes are mainly related to cancer, cell growth, which reflects the carcinogenic processes in the AA-treated rat kidneys.
2012-01-01 | GSE33703 | GEO
Project description:MicroRNAs (miRNAs) play an important role in carcinogenesis by regulating the protein translation from their targeted messenger RNAs (mRNA). Aristolochic Acid (AA) is a potent carcinogen that can induce kidney tumors in both human and experimental animals. Although the expression and roles of miRNAs have been extensively studied in cancer tissues or tissues treated by carcinogens, it is still unclear how the three levels of gene expression, including miRNA, mRNA and protein, are regulated and coordinated during the early stage of carcinogenesis. Here, we treated rats with 10 mg/kg AA or vehicle control for 12 weeks and the kidney tissues were quickly isolated and frozen immediately after the treatment. Eight kidney samples (4 for the treatment and 4 for the control) were used for analyzing miRNA and mRNA expressions with deep sequencing, and protein expressions with proteomics. MiRNA expressions were significantly changed by AA treatment. The treated samples were well separated from the control samples in both principal component analysis (PCA) and hierarchical clustering analysis (HCA). Quantitative measurements of six miRNAs using TaqMan real-time PCR were consistent with the deep sequencing results in terms of both direction and magnitude of gene expression change. Sixty-three miRNAs (adjusted p value < 0.05 and fold change > 1.5), 6,794 mRNAs (adjusted p value < 0.05 and fold change > 2.0), and 800 proteins (fold change > 2.0) were significantly altered by AA treatment. By combining the results of a computational target predicting algorithm, and the mRNA and protein expression data, 143 genes were found by the differentially expressed miRNAs (DEMs). The DEM-targeted genes are mainly related to cancer, cell growth, which reflects the carcinogenic processes in the AA-treated rat kidneys. Groups of four 6 week-old male Big Blue rats were treated with AA as its sodium salt at 10.0 mg/kg body weight by gavage (4 ml/kg body weight) 5 times a week for 12 weeks. The rats that were treated with 0.9% sodium chloride on the same schedule were used as control. microRNAs were isolated from rat kidneys and subject to next-generation sequencing to determine the expression profile.
2012-01-01 | E-GEOD-33703 | biostudies-arrayexpress
Project description:Aristolochic acid (AA) is a major ingredient in several Chinese herbs that exhibits a wide range of pharmacological effects. Recently, clinical reports and experimental studies have demonstrated that AA causes renal toxicities, acute renal failure and interstitial fibrosis.However, the molecular mechanism underlying AA nephrotoxicity is not yet fully understood. Embryonic stem cells (ESCs) are pluripotent cells isolated from early embryos, which have highly undifferentiated potential and are capable of differentiating into all kinds of body tissues and organs. It has been reported that ESCs are sensitive to drug stimulation, and thus may serve as important tools for in vitro assessment of drug toxicity. We aimed to identify accurate biomarkers of AA-induced renal toxicity on ESCs. Genomics analysis was performed to screen the changes in gene expression levels of ESCs following treatment with AA, in order to determine the potential biological processes in which AA induces renal toxicity.
2020-11-27 | GSE162195 | GEO
Project description:Aim： Use microarray analysis to understand the molecular mechanism underlying the effect of aristolochic acid (AA), a major active component of plants from the Aristolochiaceae family, in normal human kidney (HK-2) cells. Methods： HK-2 cells were treated with AA for 24 hours and cell viability was measured by a 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide assay. Complementary DNA microarrays were used to investigate the gene expression pattern of HK-2 cells exposed to AA and the results of this study were in triplicate. Quantitative real-time RT-PCR assay was used to verify the microarray data for selected nuclear factor kappa B (NF-κB)-regulated genes. Furthermore, subcellular localization of NF-κB p65 was visualized by immunofluorescence confocal microscopy in HK-2 cells. NF-κB activity was examined by luciferase reporter assay in HK-2/NF-κB transgenic cells. Results： AA exhibited a dose-dependent cytotoxic effect in HK-2 cells and induced alterations in gene expression profiles related to DNA damage response, stress response, etc. In addition, 9 biological pathways associated with immunomodulatory functions were down-regulated in AA-treated HK-2 cells. Network analysis revealed that NF-κB played a central role in the network topology. Among NF-kB-regulated genes, 8 differentially expressed genes were verified by real-time RT-PCR. The inhibition of NF-κB activity by AA was further confirmed by immunofluorescence confocal microscopy and by NF-κB luciferase reporter assay. Conclusion： Our data revealed that AA could suppress NF-κB activity in normal human cells, perhaps partially accounting for the reported anti-inflammatory effects of some plants from the genus Aristolochia. HK-2 cells were grown in keratinocyte serum-free basal medium (Gibco) supplemented with 5 ng/ml of recombinant epidermal growth factor and 50 μg/ml of bovine pituitary extract without antibiotics in 5 % CO2 at 370C. HK-2 cells were seeded in 25-T flasks and incubated for 24 h before aristolochic acid treatment. Aristolochic acid (10 90 μM) were added to HK-2 cells for 24 h. The control cells received equal amounts of water only.
2010-09-24 | E-GEOD-18243 | biostudies-arrayexpress