Dataset Information

Persistent microRNA-gene networks in primary human hepatocytes upon withdrawal of aflatoxin B1 exposure are related to hepatocellular carcinoma [miRNA]

ABSTRACT: Hepatocellular carcinoma (HCC), one of the most common cancer types, is a multi-factorial disease. One strongly associated factor is oral exposure to the food-contaminant aflatoxin B1 (AFB1). A clear link between AFB1-induced p53 mutations and HCC exists, however less is known about the association with microRNA expression changes. In particular, irreversible adverse effects that may occur at the transcriptomic level following repetitive exposure have not been investigated yet. Therefore, in this study, we aimed to dissect persistent changes in expression of microRNA-directed regulatory networks from transient transcriptome modifications contributing to AFB1-induced HCC. Primary human hepatocytes were exposed to 1 µM of AFB1 for 5 days followed by a 3 day wash-out period. Whole genome transcriptomic analysis and microRNA expressions were analyzed applying microarray technologies. By evaluating genes which remain significantly expressed into the same direction after the 3-day wash-out period persistent AFB1-induced and HCC-related biological processes could be identified. Persistent genes could be linked with "Drug and energy metabolism" and "Pre-, post- and transcriptional regulation of gene expression" related processes. Especially, two HCC-related microRNAs, hsa-miR-34b-5p and hsa-miR-222-3p, which are persistently expressed, seem to regulate genes involved in these very characteristic AFB1-induced processes referring to cancer-associated metabolism changes and regulation of gene expression. Moreover, hsa-miR-34a-5p, hsa-miR-96-5p and hsa-miR-30a-3p which become differentially expressed only upon terminating AFB1 exposure, seem to regulate persistently expressed genes. The findings within this study therefore contribute to a better understanding of the AFB1-induced onset of HCC by causing persistent effects on microRNA and gene expression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE71540 | GEO | 2018/12/31

REPOSITORIES: GEO

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Project description:The molecular response to hypoxia is a critical cellular process implicated in cancer, and a target for drug development. The activity of the major player, HIF1α, is regulated at different levels, including the transcriptional level by the Ets factor ELK3. The molecular mechanisms of this intimate transcriptional connection remain largely unknown. Whilst investigating global ELK3-chromatin interactions, we uncovered an unexpected connection that involves the microRNA hsa-miR-155-5p, a hypoxia-inducible oncomir that targets HIF1α. One of the ELK3 chromatin binding sites, detected by Chromatin Immuno-Precipitation Sequencing (ChIP-seq) of normal Human Umbilical Vein Endothelial Cells (HUVEC), is located at the transcription start site of the MIR155HG genes that expresses hsa-miR-155-5p. We confirmed that ELK3 binds to this promoter by ChIP and QPCR. We showed that ELK3 and hsa-miR-155-5p form a double-negative regulatory loop. ELK3 depletion induced hsa-miR-155-5p expression, and hsa-miR-155-5p expression decreased ELK3 expression at the RNA level through a conserved target sequence in its 3’-UTR. We further showed that the activities of hsa-miR-155-5p and ELK3 are functionally linked. Pathway analysis indicates that both factors are implicated in related processes, including cancer and angiogenesis. hsa-miR-155-5p expression and ELK3 depletion have similar effects on expression of known ELK3 target genes, and in-vitro angiogenesis and wound closure. Bioinformatic analysis of cancer RNA-seq data shows that hsa-miR-155-5p and ELK3 expression are significantly anti-correlated, as would be expected from hsa-miR-155-5p targeting ELK3 RNA. Hypoxia (0% oxygen) down-regulates ELK3 mRNA in a microRNA and hsa-miR-155-5p dependent manner. These results tie ELK3 into the hypoxia response pathway through an oncogenic microRNA and into a circuit implicated in the dynamics of the hypoxic response. This crosstalk could be important in the development of new treatments for a range of pathologies.

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Persistent microRNA-gene networks in primary human hepatocytes upon withdrawal of aflatoxin B1 exposure are related to hepatocellular carcinoma [miRNA]

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