Arsenic-induced Gene Expression Research Articles

Identification of therapeutic miRNAs from the arsenic induced gene expression profile of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer, with a rising worldwide burden due to a lack of efficient treatment techniques and diagnosis after it has metastasized. Therefore, small non-coding RNA (miRNAs) as protein translation inhibitors are gaining attention that degrades or suppress specific gene transcripts, making it a prime strategy for oncogenes or tumor suppression. Systematic research with miRNAs in combination with Arsenic, which has been employed as a drug to treat several diseases, including cancer, was focused on cellular responses through interacting with multiple biological targets. The differential gene expression of the DNA microarray dataset (GSE48441) revealed the association of sterol, cholesterol, and lipid metabolic processes. With the aid of the network pharmacology approach, hsa-mir-335-5p was uncovered to negatively regulate the important nodes driving the transport and utilization of essential compounds for the rapid growth and proliferation of cancer cells. The binding energies of the duplexes were validated by the minimal free energies of the mRNAs for hsa-mir-335-5p, indicating energetically desirable binding association. The molecular interactions between hsa-mir-335-5p, which interacts with the Argonaute protein in the RNA induced silencing complex, and the target-specific genes were also investigated, revealing its susceptibility to be employed in in vitro studies.

The SLIM1 transcription factor is required for arsenic resistance in Arabidopsis thaliana.

The transcriptional regulators of arsenic-induced gene expression remain largely unknown. Sulfur assimilation is tightly linked with arsenic detoxification. Here, we report that mutant alleles in the SLIM1 transcription factor are substantially more sensitive to arsenic than cadmium. Arsenic treatment caused high levels of oxidative stress in the slim1 mutants, and slim1 alleles were impaired in both thiol accumulation and sulfate accumulation. We further found enhanced arsenic accumulation in roots of slim1 mutants. Transcriptome analyses indicate an important role for SLIM1 in arsenic-induced tolerance mechanisms. The present study identifies the SLIM1 transcription factor as an essential component in arsenic tolerance and arsenic-induced gene expression. Our results suggest that the severe arsenic sensitivity of the slim1 mutants is caused by altered redox status.

An amiRNA screen uncovers redundant CBF and ERF34/35 transcription factors that differentially regulate arsenite and cadmium responses.

Arsenic stress causes rapid transcriptional responses in plants. However, transcriptional regulators of arsenic-induced gene expression in plants remain less well known. To date, forward genetic screens have proven limited for dissecting arsenic response mechanisms. We hypothesized that this may be due to the extensive genetic redundancy present in plant genomes. To overcome this limitation, we pursued a forward genetic screen for arsenite tolerance using a randomized library of plants expressing >2,000 artificial microRNAs (amiRNAs). This library was designed to knock-down diverse combinations of homologous gene family members within sub-clades of transcription factor and transporter gene families. We identified six transformant lines showing an altered response to arsenite in root growth assays. Further characterization of an amiRNA line targeting closely homologous CBF and ERF transcription factors show that the CBF1,2 and 3 transcription factors negatively regulate arsenite sensitivity. Furthermore, the ERF34 and ERF35 transcription factors are required for cadmium resistance. Generation of CRISPR lines, higher-order T-DNA mutants and gene expression analyses, further support our findings. These ERF transcription factors differentially regulate arsenite sensitivity and cadmium tolerance.

Arsenic induced gene expression changes in primary human uroepithelial cells

Arsenic induced gene expression changes in primary human uroepithelial cells

Combined in utero and juvenile exposure of mice to arsenate and atrazine in drinking water modulates gene expression and clonogenicity of myeloid progenitors

The effects of arsenate (As) and atrazine (Atr) on myeloid progenitors (colony-forming unit-granulocyte /macrophage, CFU-GM) cells derived from bone marrow were studied in male and female mice after combined in utero and juvenile exposure. Female adult mice were treated with arsenate in drinking water during gestation. Then, separate groups of males and females’ offspring were exposed for 4 months to atrazine, to additional arsenate or to co-exposure of atrazine and arsenate together in drinking water. In male mice, arsenate and the combined exposure did not modulate the percentage of CFU-GM progenitors, whereas atrazine significantly decreases the clonogenicity of myeloid cells. In females, the percentage of CFU-GM significantly decreased after atrazine exposure did not change with arsenate treatment, but dramatically increased after the combined exposure. The expression of estrogen receptors alpha (ERα) and beta (ERβ) in bone marrow cells was investigated, and an up-regulation of receptor beta was observed in both genders. A gene expression profile was generated using nylon membranes spotted with 1185 cancer-related genes. Results from microarrays indicate that atrazine alone did not stimulate the expression of any of the genes analysed in both male and female. Arsenic induced gene expression modulation only in female. Major significant changes on the gene expression resulted following the co-exposure to arsenic and atrazine in both male and female.

Gene Expression Changes and Induction of Cell Proliferation by Chronic Exposure to Arsenic of Mouse Testicular Leydig Cells

Arsenic is an important environmental carcinogen that affects millions of people worldwide through contaminated water supplies. Chronic exposure of arsenic has been shown to induce malignant transformation of mammalian cells; however, the mechanism underlying arsenic-induced carcinogenesis is not clear. The (1) induction in the cell proliferation, (2) decrease in DNA repair capacity resulting in the accumulation of mutations, and (3) changes in the DNA methylation patterns affecting regulation of genes are hallmarks of cancer development. Thus, the purpose of this study was to determine whether long-term exposure of both low and high concentrations of arsenic can perturb cell proliferation, DNA repair, and the maintenance of DNA methylation status in TM3 cells, an immortalized Leydig cell derived from normal mouse testis. The effect of arsenic on cell proliferation was determined by cell count data, and arsenic-induced gene expression changes were measured by quantitative real-time polymerase chain reduction (PCR). The results this study revealed a concentration-dependent induction of cell proliferation by arsenic. Increased expression of cell proliferation marker genes (PCNA, CyclinD1) and DNA methylation (DNA Methyl Transferase I) and decreased expression of genes for DNA repair (DNA Polymerase β, ERCC6) with lower concentrations of arsenic was also observed. Thus, the findings of this study are novel, as they indicate a mechanism for arsenic-induced cancers. This is based on the observed increase in cell proliferation and decrease in the capacity of cells to maintain its genomic stability. Our study provides the evidence that arsenic may play a role in the etiology of testicular cancer.

Arsenic-induced gene expression changes in the neural tube of folate transport defective mouse embryos

Arsenic injected intraperitoneally (i.p.) during early organogenesis to small pregnant laboratory rodents (mouse, rat, and hamster) induces several congenital defects in the progeny. Among those abnormalities consistently and predominantly observed are exencephaly and encephalocele. These severe defects of the central nervous system originate from a corrupted process of neurulation and are better known as neural tube defects (NTDs). In order to understand the mechanism of arsenate-induced NTDs, we designed studies in which highly sensitive Folr2 nullizygous mice were injected intraperitoneally with sodium arsenate at the beginning of the neural tube formation process. This specific knockout mouse and the arsenic exposure conditions were chosen as they were known to provide a high incidence of exencephaly in exposed embryos. We have applied gene expression technology to the anterior neural tube. This allowed us to study arsenic-induced changes in patterns of gene expression that may contribute to the development of neural tube defects in these mice. Using extensive data analysis approaches including hierarchical clustering and gene ontology analysis, we identified several candidate genes as well as important ontology groups that may be responsible for arsenic's teratogenicity. Changes in the expression of several genes in response to arsenic treatment in our model had previously been demonstrated by other investigators to also induce NTDs in murine model systems. These include: engrailed 1 ( En- 1), platelet derived growth factor receptor alpha ( Pdgfrα) and ephrinA7 ( EphA7). We also found several gene ontology groups that could be implicated in arsenic's underlying teratogenicity: morphogenesis, oxidative phosporylation, redox response, and regulation of I-kappaB kinase/NF-kappaB cascade. Additionally, we revealed new target genes which may be responsible for arsenic disrupted oxidative phosphorylation.