MicroRNAs, diet, and cancer: New mechanistic insights on the epigenetic actions of phytochemicals

Department of Environmental and Molecular Toxicology, and Linus Pauling Institute, Oregon State University, Corvallis, Oregon, USA.
Molecular Carcinogenesis (Impact Factor: 4.81). 03/2012; 51(3):213-30. DOI: 10.1002/mc.20822
Source: PubMed


There is growing interest in the epigenetic mechanisms that impact human health and disease, including the role of microRNAs (miRNAs). These small (18-25 nucleotide), evolutionarily conserved, non-coding RNA molecules regulate gene expression in a post-transcriptional manner. Several well-orchestered regulatory mechanisms involving miRNAs have been identified, with the potential to target multiple signaling pathways dysregulated in cancer. Since the initial discovery of miRNAs, there has been progress towards therapeutic applications, and several natural and synthetic chemopreventive agents also have been evaluated as modulators of miRNA expression in different cancer types. This review summarizes the most up-to-date information related to miRNA biogenesis, and critically evaluates proposed miRNA regulatory mechanisms in relation to cancer signaling pathways, as well as other epigenetic modifications (DNA methylation patterns, histone marks) and their involvement in drug resistance. We also discuss the mechanisms by which dietary factors regulate miRNA expression, in the context of chemoprevention versus therapy.

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Available from: Roderick Dashwood, Aug 18, 2014
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    • "The majority of these studies have utilized in vitro culture systems to examine the effects of dietary constituents on miRNA expression. The few whole-animal studies that have been conducted have shown promise in their abilities to modulate miRNA expression [43]. This is the first report of dietary modulation of microRNAs in a spontaneous cancer model. "
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    ABSTRACT: Background The laying hen model of spontaneous epithelial ovarian cancer (EOC) is unique in that it is the only model that enables observations of early events in disease progression and is therefore also uniquely suited for chemoprevention trials. Previous studies on the effect of dietary flaxseed in laying hens have revealed the potential for both amelioration and prevention of ovarian cancer. The objective of this study was to assess the effect of flaxseed on genes and pathways that are dysregulated in tumors. We have used a bioinformatics approach to identify these genes, followed by qPCR validation, immunohistochemical localization, and in situ hybridization to visualize expression in normal ovaries and tumors from animals fed a control diet or a diet containing 10% flaxseed. Results Bioinformatic analysis of ovarian tumors in hens led to the identification of a group of highly up-regulated genes that are involved in the embryonic process of branching morphogenesis. Expression of these genes coincides with expression of E-cadherin in the tumor epithelium. Levels of expression of these genes in tumors from flax-fed animals are reduced 40-60%. E-cadherin and miR200 are both up-regulated in tumors from control-fed hens, whereas their expression is decreased 60-75% in tumors from flax-fed hens. This does not appear to be due to an increase in ZEB1 as mRNA levels are increased five-fold in tumors, with no significant difference between control-fed and flax-fed hens. Conclusions We suggest that nutritional intervention with flaxseed targets the pathways regulating branching morphogenesis and thereby alters the progression of ovarian cancer. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-15-709) contains supplementary material, which is available to authorized users.
    BMC Genomics 08/2014; 15(1):709. DOI:10.1186/1471-2164-15-709 · 3.99 Impact Factor
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    • "It is estimated that nearly 30% of all human genes are regulated by miRNAs.26 Although non-coding RNA is essential to normal cell processes (eg introns and splicing), aberrant miRNA expression patterns are linked to chromosomal instability25 by the silencing of epigenetic regulators such as DNMTs and HDACs.6 "
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    ABSTRACT: The aim of cancer chemoprevention is disruption or delay of the molecular pathways that lead to carcinogenesis. Chemopreventive blocking and/or suppressing agents disrupt the molecular mechanisms that drive carcinogenesis such as DNA damage by reactive oxygen species, increased signal transduction to NF-κB, epigenomic deregulation, and the epithelial mesenchymal transition that leads to metastatic progression. Numerous dietary phytochemicals have been observed to inhibit the initiation phase of carcinogenesis, and therefore are useful in primary chemoprevention. Moreover, phytochemicals are capable of interfering with the molecular mechanisms of metastasis. Likewise, numerous synthetic compounds are relevant and clinically viable as chemopreventive agents during the fundamental stages of carcinogenesis. While molecularly targeted anti-cancer therapies are in constant stages of development, superior patient outcomes are observed if carcinogenic processes are prevented altogether. This article reviews the role of chemopreventive compounds in inhibition of cancer initiation and their ability to reduce cancer progression.
    Cancer Growth and Metastasis 06/2014; 7:19-25. DOI:10.4137/CGM.S11288
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    • "MicroRNAs (miRNAs or miRs) influence multiple stages of cancer development, via post-transcriptional mechanisms that degrade or repress target messenger RNAs (mRNAs) [1]. Several miRNAs with critical roles in early embryonic development [2] become aberrantly expressed in tumors [3]. "
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    ABSTRACT: Background MicroRNAs (miRNAs or miRs) are short non-coding RNAs that affect the expression of genes involved in normal physiology, but that also become dysregulated in cancer development. In the latter context, studies to date have focused on high-abundance miRNAs and their targets. We hypothesized that among the pool of low-abundance miRNAs are some with the potential to impact crucial oncogenic signaling networks in colon cancer. Results Unbiased screening of over 650 miRNAs identified miR-206, a low-abundance miRNA, as the most significantly altered miRNA in carcinogen-induced rat colon tumors. Computational modeling highlighted the stem-cell marker Krüppel-like factor 4 (KLF4) as a potential target of miR-206. In a panel of primary human colon cancers, target validation at the mRNA and protein level confirmed a significant inverse relationship between miR-206 and KLF4, which was further supported by miR-206 knockdown and ectopic upregulation in human colon cancer cells. Forced expression of miR-206 resulted in significantly increased cell proliferation kinetics, as revealed by real-time monitoring using HCT116 cells. Conclusions Evolutionarily conserved high-abundance miRNAs are becoming established as key players in the etiology of human cancers. However, low-abundance miRNAs, such as miR-206, are often among the most significantly upregulated miRNAs relative to their expression in normal non-transformed tissues. Low-abundance miRNAs are worthy of further investigation, because their targets include KLF4 and other pluripotency and cancer stem-cell factors.
    09/2012; 4(1). DOI:10.1186/1868-7083-4-16
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