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Analysis of Combinatorial miRNA Treatments to Regulate Cell Cycle and Angiogenesis
Published on: March 30, 2019
Regulation of cellular Cyclin D1 gene by arsenic is mediated through miR-2909
1Experimental Medicine & Biotechnology Department, Postgraduate Institute of Medical Education & Research, Chandigarh-160012, India.
Abstract:
Arsenic through its ability to regulate genes that link cell cycle control with apoptosis has been widely recognized to play a crucial role in oncogenomics. However, the molecular event by which arsenic affects such genes is far from clear. Here we provide reasonably good evidence to support the view that arsenic exposure to human PBMCs (peripheral blood mononuclear cells) at low concentrations results in the over-expression of miR-2909 within these cells. This over-expressed miR-2909 was found to regulate CCND1 (Cyclin D1) gene expression, within these cells by inducing splice-switching of tumor suppresser CYLD (Cylindromatosis) gene as well as modulation of SP1 (Specificity Protein 1) activity through the repression of KLF4 (Kruppel-like factor4) expression at the translational level. Arsenic dependent regulation of AATF (Apoptosis Antagonizing Transcription factor) and BCL3 (B-cell Lymphoma 3) were also found to be modulated through its capacity to induce miR-2909 expression. Based upon these observations, a novel epigenomic pathway was proposed which may not only be useful in understanding the paradoxical role of arsenic in oncogenomics but also may even be useful in devising various strategies for the treatment/prevention of tumors induced by arsenic.
Insights
Low-dose arsenic exposure in human cells increases miR-2909, impacting oncogenomics by regulating genes involved in cell cycle control and apoptosis. This discovery reveals a novel epigenomic pathway for arsenic-induced tumors.
Area of Science:
- * Oncogenomics and Epigenetics
- * Molecular Biology and Toxicology
Background:
- * Arsenic is known to influence oncogenomics by regulating genes controlling cell cycle and apoptosis.
- * The precise molecular mechanisms by which arsenic affects these genes remain unclear.
Purpose of the Study:
- * To investigate the molecular events linking arsenic exposure to oncogenomic alterations.
- * To elucidate the role of microRNAs in arsenic-induced gene regulation.
Main Methods:
- * Exposure of human peripheral blood mononuclear cells (PBMCs) to low concentrations of arsenic.
- * Analysis of gene and microRNA expression levels, including miR-2909, CCND1, CYLD, SP1, KLF4, AATF, and BCL3.
- * Investigation of translational and splice-switching regulatory mechanisms.
Main Results:
- * Arsenic exposure at low concentrations leads to the over-expression of miR-2909 in human PBMCs.
- * miR-2909 regulates Cyclin D1 (CCND1) gene expression by inducing splice-switching of the CYLD gene.
- * miR-2909 modulates Specificity Protein 1 (SP1) activity via repression of Kruppel-like factor 4 (KLF4) at the translational level.
- * Arsenic-induced miR-2909 expression also affects Apoptosis Antagonizing Transcription factor (AATF) and B-cell Lymphoma 3 (BCL3) regulation.
Conclusions:
- * A novel epigenomic pathway involving miR-2909 is proposed to explain arsenic's role in oncogenomics.
- * This pathway provides insights into the paradoxical effects of arsenic in cancer development.
- * The findings may aid in developing strategies for preventing or treating arsenic-induced tumors.
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