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Tissue-specific response of microRNAs to carcinogenicity and mutagenicity of aristolochic acid in rats

ABSTRACT: 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.

ORGANISM(S): Mus musculus Rattus norvegicus Homo sapiens

PROVIDER: GSE50946 | GEO | 2013/11/10

SECONDARY ACCESSION(S): PRJNA219409

REPOSITORIES: GEO

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Project description:Li-Fraumeni syndrome (LFS) is a disorder due to inherited mutations in the TP53 gene resulting in an increased risk of developing several types of cancer. MicroRNA miR-34a has been implicated downstream of p53 on the basis of being a direct transcriptional target and, when over-expressed, having pro-apoptotic phenotypes in cell lines. Moreover, miR-34a has been shown to be a modifier gene in the context of LFS, since its epigenetic silencing increases the likelihood of tumour development in patients with mutant TP53. However, the in vivo consequences of miR-34 loss are still unclear. For example, mice lacking all three (a,b,c) miR-34 homologs show no detectable abnormalities in p53 responses. The relative expression of different miR-34 genes in zebrafish was studied using qRT-PCR with specific assays. The miR-34a, miR-34b and miR-34c display unique onset of developmental expression and expression levels, with miR-34a being the most abundant and constant in expression. All of the miR-34 genes also showed clear induction by p53 when DNA-damaging treatments are performed. Using CRISPR-Cas9 technology, we generated a zebrafish miR-34a deletion mutant to further investigate the roles of miR-34a on its own and its association with the p53 pathway. Predictably, a miR-34a deletion mutant demonstrated absence of miR-34a, though without miR-34b and miR-34c compensation beyond baseline expression levels. Mutants survive to adulthood, show no overt phenotypes and have normal apoptotic responses to DNA-damaging irradiation or camptothecin treatments. To further explore the effects of miR-34a, we performed gene expression profiling using RNA-seq of wild-type and miR-34a deletion mutant zebrafish embryos at 8 hpf. This experiment was motivated by a previous report knock-down of miR-34a in zebrafish leads to dramatic increases in expression of miR-34a target genes. We therefore expected that this experiment will help define the set of miR-34a target genes. The results of this RNA-seq experiment showed that the loss of miR-34a led to large transcriptomic effects at 8 hpf (1573 genes UP and 1679 genes DOWN at 1.5-fold change and FDR < 0.05). There was no significant enrichment of predicted miR-34a target genes among the differentially regulated genes but some interesting biological trends were found and will be described in the paper associated with this dataset.

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Tissue-specific response of microRNAs to carcinogenicity and mutagenicity of aristolochic acid in rats

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